Modulators of mas-related g-protein receptor x2 and related products and methods

ABSTRACT

Methods are provided for modulating MRGPRX2 generally, or for treating a MRGPRX2 dependent condition more specifically, by contacting the MRGPRX2 or administering to a subject in need thereof, respectively, an effective amount of a compound having structure (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein A, B, C, D, E, G, W, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined herein. Pharmaceutical compositions containing such compounds, as well as the compounds themselves, are also provided.

BACKGROUND Technical Field

The invention relates to modulators of the Mas-related G-protein coupledreceptor X2, to products containing the same, as well as to methods oftheir use and preparation.

Description of the Related Art

Mas-related G-protein receptors (MRGPRs) are a group of orphan receptorswith limited expression in very specialized tissues. Very little isknown about the function of most of these receptors. There are eightrelated receptors in this class expressed in humans, only four of whichhave readily identifiable orthologs in other species (i.e., MRGPR D, E,F and G). Other than humans, members of MRGPR subfamily X receptors(MRGPR X1, X2, X3 and X4) have been detected in primates, includingmacaques and rhesus monkeys, and more recently dogs and horses, but theydo not have a single corresponding ortholog in rodents.

BRIEF SUMMARY

This invention is based, in part, on the identification of MRGPRX2 orMRGPRX2 ortholog modulator compounds. MRGPRX2 corresponds functionallyto mouse MRGPRB2 and dog MRGPRX2 in mast cells. MRGPRX2 and its orthologreceptors mediate disorders including pseudo-allergic reactionsincluding pseudo-allergic drug reactions, chronic itch (e.g., pruritus),inflammation disorders, pain disorders, skin disorders, wound healing,cardiovascular disease, and lung inflammation/COPD. In one embodiment,both MRGPRB2 and MRGPRX2 expression is largely restricted to mast cells.Mast cells are innate immune cells that primarily reside at sitesexposed to the external environment, such as the skin,oral/gastrointestinal mucosa and respiratory tract. Mast cells expressnumerous receptors that respond to mechanical and chemical stimuli. Uponactivation, classically by IgE, mast cells release pre-formed mediatorsfrom granules (e.g., histamine, proteases, and heparin) and newlysynthesized mediators (e.g., thromboxane, prostaglandin D2, leukotrieneC4, tumor necrosis factor alpha, eosinol chemotactor factor, andplatelet-activating factor) that elicit allergic and inflammatoryresponses. Histamine dilates post-capillary venules, activates theendothelium, and increases blood vessel permeability. This causes localedema, warmth, redness, and chemotaxis of other inflammatory cells tothe site of release. Histamine also contributes to neuronalsensitization that leads to pain or itch. MRGPRB2 and MRGPRX2 mediateimmunoglobulin E (IgE) independent activation of mast cells. MRGPRB2 andMRGPRX2 are receptors for (or sensitive to activation by) variousligands, including basic secretagogues (small cationic molecules),certain drugs (e.g., cationic peptidergic drugs), neuropeptides, andantimicrobial peptides, and thus are important for non-IgE mediatedpseudo-allergic reactions, inflammation, pain, and itch conditions. Mastcells may also contribute to the progression of autoimmune disorders bypromoting chronic inflammation in the local tissue microenvironment andultimately polarizing toward a T_(h)17 immune response. Thus, modulatingMRGPRX2 or MRGPRX2 ortholog allows for treatment of autoimmune diseases,pseudo-allergic drug reactions, pain, itch, and inflammatory disorderssuch as inflammatory bowel disease, urticaria, sinusitis, asthma,rosacea, endometriosis, and other MRGPRX2 or MRGPRX2 ortholog dependentconditions as explained in more detail below.

In one embodiment, a method is provided for treating a MRGPRX2 or aMRGPRX2 ortholog dependent condition by administering to a subject inneed thereof an effective amount of the pharmaceutical composition ofthe modulator compounds of the present invention.

Accordingly, in an embodiment, is provided a compound having structure(I):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof, wherein A, B, C, D, E, G, W, Y, Z, R¹, R², R³, R⁴, R⁵,R⁶, R⁷ and R⁸ are as defined herein.

In other embodiments, compounds are provided having any of thestructures (Ia), (Ia′), (Ib), (Ic) or (Id) as defined herein, or apharmaceutically acceptable salt, isomer, hydrate, solvate or isotopethereof.

In yet other embodiments, pharmaceutical compositions are providedcomprising a carrier or excipient and a compound having structure (I),or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof.

In other embodiments, pharmaceutical compositions are providedcomprising substructures of structure (I) with structures (Ia), (Ia′),(Ib), (Ic) or (Id) as defined herein or a pharmaceutically acceptablesalt, isomer, hydrate, solvate or isotope thereof.

In another embodiment, methods are provided for treating an MRGPRX2 orMRGPRX2 ortholog dependent condition by administering to a subject inneed thereof an effective amount of a compound having structure (I), ora pharmaceutically acceptable salt, isomer, hydrate, solvate or isotopethereof.

In some embodiments, the MRGPRX2 or MRGPRX2 ortholog dependent conditionis one or more of a pseudo-allergic reaction, itch associated condition,a pain associated condition, an inflammation-associated condition, or anautoimmune disorder.

In one embodiment, the methods of treating the MRGPRX2 or MRGPRX2ortholog dependent condition are provided which comprise administeringan effective amount of a compound of structure (I) or any of thestructures (Ia), (Ia′), (Ib), (Ic) or (Id) as defined herein or apharmaceutically acceptable salt, isomer, hydrate, solvate or isotopethereof.

In another embodiment, compounds are provided having one or more of thestructures disclosed herein, or a pharmaceutically acceptable salt,isomer, hydrate, solvate or isotope thereof.

DETAILED DESCRIPTION

As mentioned above, the invention relates to modulators of the MRGPRX2,to products containing the same, as well as to methods of their use andpreparation. This invention is based, in part, on the identificationMRGPRX2 modulator compounds. Both MRGPRB2 and MRGPRX2 are expressed inmast cells and dorsal root ganglia. Both MRGPRX2 and MRGPRB2 arereceptors for (or sensitive to activation by) a diverse group ofligands, including basic secretagogues, certain drugs, neuropeptides,antimicrobial peptides, and thus are important for pseudo-allergicreactions, itch, pain, or inflammatory disorders upon exposure.

MRGPRs appear to be sensory receptors that recognize their externalenvironment to exogenous or endogenous signals/chemicals. Thesereceptors likely respond to multiple chemical ligands/agonists. Forexample, MRGPRX2 recognizes Compound 48/80, Substance P, mastoparan,icatibant, ciprofloxacin, and tracurium, as agonist signals. In certainembodiments, molecules of this invention modulate MRGPRX2 by functioningas inverse agonists that are capable of blocking multiple chemicalentities, and/or as competitive antagonists that can specifically blockindividual ligands. In one embodiment, such modulations are selectiveagainst other MRGPRs, such as MRGPRX1, X3 and/or X4.

Definitions

As used herein, the following terms have the meaning defined below,unless the context indicates otherwise.

“Modulating” MRGPRX2 means that the compound interacts with the MRGPRX2in a manner such that it functions as an inverse agonist to thereceptor, and/or as a competitive antagonist to the receptor. In oneembodiment, such modulation is partially or fully selective againstother MRGPRs, such as MRGPRX1, X3 and/or X4.

“MRGPR” refers to one or more of the Mas-related G protein coupledreceptors, which are a group of orphan receptors with limited expressionin very specialized tissues (e.g., in mast cells and dorsal rootganglia) and barrier tissues. There are eight related receptors in thisclass expressed in humans, only 4 of which have readily identifiableorthologs in other species (i.e., MRGPR D, E, F and G). The other fourreceptors (MRGPR X1, X2, X3 and X4) have counterparts in higher speciesincluding monkeys, dogs and horses, but they do not have a singlecorresponding ortholog in rodents.

“MRGPRX2,” also referred to as “MRGX2,” or “MGRG3,” refers to a memberof the MRGPR family that is expressed on mast cells and capable ofmediating IgE independent activation (e.g., mast cell degranulation) inresponse to ligand binding. An exemplary human MRGPRX2 amino acidsequence is set forth in Uniprot Q96LB1.

“MRGPRX2 ortholog” refers to genes in non-human species including dogsand horses that have evolved through speciation events. Orthologs ofhuman MRGPRX2 are determined by expression pattern and pharmacology.Studies of non-human species MRGPRX2 show gene clusters containing somehuman MRGPRX2 members, some with coding genes, and some showing sequenceidentity to human MRGPRX2.

“Effective amount” refers to a quantity of a specified agent sufficientto achieve a desired effect in a subject being treated with that agent.Ideally, an effective amount of an agent is an amount sufficient toinhibit or treat the disease without causing substantial toxicity in thesubject. The effective amount of an agent will be dependent on thesubject being treated, the severity of the affliction, and the manner ofadministration of the pharmaceutical composition. Methods of determiningan effective amount of the disclosed compound sufficient to achieve adesired effect in a subject will be understood by those of skill in theart in light of this disclosure.

“Alkyl” means a saturated or unsaturated straight chain or branchedalkyl group having from 1 to 8 carbon atoms, in some embodiments from 1to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and insome embodiments from 1 to 3 carbon atoms. Examples of saturatedstraight chain alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, n-butyl, n-pentyl-, n-hexyl, n-heptyl, and n-octylgroups. Examples of branched alkyl groups include, but are not limitedto, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. An unsaturated alkyl includes alkenyl andalkynyl as defined below.

“Alkenyl” means a straight chain or branched alkenyl group having from 2to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in someembodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to3 carbon atoms. Alkenyl groups are unsaturated hydrocarbons that containat least one carbon-carbon double bond. Examples of lower alkenyl groupsinclude, but are not limited to, vinyl, propenyl, butenyl, pentenyl, andhexenyl.

“Alkynyl” means a straight chain or branched alkynyl group having from 2to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in someembodiments from 2 to 4 carbon atoms, and in some embodiments from 2 to3 carbon atoms. Alkynyl groups are unsaturated hydrocarbons that containat least one carbon-carbon triple bond. Examples of alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,and hexynyl.

“Halo” or “halogen” refers to fluorine, chlorine, bromine, and iodine.

“Hydroxy” refers to —OH.

“Cyano” refers to —CN.

Amino refers to —NH₂, —NHalkyl or N(alkyl)₂, wherein alkyl is as definedabove. Examples of amino include, but are not limited to —NH₂, —NHCH₃,—N(CH₃)₂, and the like.

“Haloalkyl” refers to alkyl as defined above with one or more hydrogenatoms replaced with halogen. Examples of lower haloalkyl groups include,but are not limited to, —CF₃, —CHF₂, and the like.

“Alkoxy” refers to alkyl as defined above joined by way of an oxygenatom (i.e., —O-alkyl). Examples of alkoxy groups include, but are notlimited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy,sec-butoxy, tert-butoxy, and the like.

“Haloalkoxy” refers to haloalkyl as defined above joined by way of anoxygen atom (i.e., —O-haloalkyl). Examples of lower haloalkoxy groupsinclude, but are not limited to, —OCF₃, and the like.

“Cycloalkyl” refers to alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring do notgive rise to aromaticity. Examples of cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like.

“Aryl” groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Representative aryl groups include, but are not limited to,phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments,aryl groups contain 6-14 carbons in the ring portions of the groups. Theterms “aryl” and “aryl groups” include fused rings wherein at least onering, but not necessarily all rings, are aromatic, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like). In one embodiment, aryl is phenyl or naphthyl, and in anotherembodiment aryl is phenyl.

“Carbocycle” refers to alkyl groups forming a ring structure, which canbe substituted or unsubstituted, wherein the ring is either completelysaturated, partially unsaturated, or fully unsaturated, wherein if thereis unsaturation, the conjugation of the pi-electrons in the ring maygive rise to aromaticity. In one embodiment, carbocycle includescycloalkyl as defined above. In another embodiment, carbocycle includesaryl as defined above.

“Heterocycle” refers to aromatic and non-aromatic ring moietiescontaining 3 or more ring members, of which one or more is a heteroatomsuch as, but not limited to, N, O, S, or P. In some embodiments,heterocyclyl include 3 to 20 ring members, whereas other such groupshave 3 to 15 ring members. At least one ring contains a heteroatom, butevery ring in a polycyclic system need not contain a heteroatom. Forexample, a dioxolanyl ring and a benzdioxolanyl ring system(methylenedioxyphenyl ring system) are both heterocyclyl groups withinthe meaning herein.

Heterocyclyl groups also include fused ring species including thosehaving fused aromatic and non-aromatic groups. A heterocyclyl group alsoincludes polycyclic ring systems containing a heteroatom such as, butnot limited to, quinuclidyl, and also includes heterocyclyl groups thathave substituents, including but not limited to alkyl, halo, amino,hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one ofthe ring members. A heterocyclyl group as defined herein can be aheteroaryl group or a partially or completely saturated cyclic groupincluding at least one ring heteroatom. Heterocyclyl groups include, butare not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl,dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl,thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

In one embodiment, heterocyclyl includes heteroaryl.

“Heteroaryl” refers to aromatic ring moieties containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl,pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl,triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, andquinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups”include fused ring compounds such as wherein at least one ring, but notnecessarily all rings, are aromatic, including tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl, and 2,3-dihydro indolyl.

“Isomer” is used herein to encompass all chiral, diastereomeric orracemic forms of a structure (also referred to as a stereoisomer, asopposed to a structural or positional isomer), unless a particularstereochemistry or isomeric form is specifically indicated. Suchcompounds can be enriched or resolved optical isomers at any or allasymmetric atoms as are apparent from the depictions, at any degree ofenrichment. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers can be synthesized so as to be substantiallyfree of their enantiomeric or diastereomeric partners, and these are allwithin the scope of certain embodiments of the invention. The isomersresulting from the presence of a chiral center comprise a pair ofnonsuperimposable-isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active (i.e., they arecapable of rotating the plane of plane polarized light and designated Ror S).

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.For example, the isolated isomer may be at least about 80%, at least 80%or at least 85% pure by weight. In other embodiments, the isolatedisomer is at least 90% pure or at least 98% pure, or at least 99% pureby weight.

“Substantially enantiomerically or diastereomerically” pure means alevel of enantiomeric or diastereomeric enrichment of one enantiomerwith respect to the other enantiomer or diastereomer of at least about80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%,99.5% or 99.9%.

The terms “racemate” and “racemic mixture” refer to an equal mixture oftwo enantiomers. A racemate is labeled “(±)” because it is not opticallyactive (i.e., will not rotate plane-polarized light in either directionsince its constituent enantiomers cancel each other out). All compoundswith an asterisk (*) adjacent to a tertiary or quaternary carbon areoptically active isomers, which may be purified from the respectiveracemate and/or synthesized by appropriate chiral synthesis.

A “hydrate” is a compound that exists in combination with watermolecules. The combination can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form; that is, a compound in a water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is similar to a hydrate except that a solvent other thatwater is present. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form; that is,a compound in a solvent solution, while it may be solvated, is not asolvate as the term is used herein.

“Isotope” refers to atoms with the same number of protons but adifferent number of neutrons, and an isotope of a compound of structure(I) includes any such compound wherein one or more atoms are replaced byan isotope of that atom. For example, carbon 12, the most common form ofcarbon, has six protons and six neutrons, whereas carbon 13 has sixprotons and seven neutrons, and carbon 14 has six protons and eightneutrons. Hydrogen has two stable isotopes, deuterium (one proton andone neutron) and tritium (one proton and two neutrons). While fluorinehas a number of isotopes, fluorine-19 is longest-lived. Thus, an isotopeof a compound having the structure of structure (I) includes, but notlimited to, compounds of structure (I) wherein one or more carbon 12atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one ormore hydrogen atoms are replaced with deuterium and/or tritium, and/orwherein one or more fluorine atoms are replaced by fluorine-19.

“Salt” generally refers to an organic compound, such as a carboxylicacid or an amine, in ionic form, in combination with a counter ion. Forexample, salts formed between acids in their anionic form and cationsare referred to as “acid addition salts”. Conversely, salts formedbetween bases in the cationic form and anions are referred to as “baseaddition salts.”

The term “pharmaceutically acceptable” refers an agent that has beenapproved for human consumption and is generally non-toxic. For example,the term “pharmaceutically acceptable salt” refers to nontoxic inorganicor organic acid and/or base addition salts (see, e.g., Lit et al., SaltSelection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986)(incorporated by reference herein).

Pharmaceutically acceptable base addition salts of compounds of theinvention include, for example, metallic salts including alkali metal,alkaline earth metal, and transition metal salts such as, for example,calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceuticallyacceptable base addition salts also include organic salts made frombasic amines such as, for example, N,N′dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine.

Pharmaceutically acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of inorganic acidsinclude hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids,examples of which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic,embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic,p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic,alginic, βhydroxybutyric, salicylic, galactaric, and galacturonic acid.

The compounds of the disclosure (i.e., compounds of structure (I) andembodiments thereof), or their pharmaceutically acceptable salts maycontain one or more centers of geometric asymmetry and may thus giverise to enantiomers, diastereomers, and other stereoisomeric forms thatare defined, in terms of absolute stereochemistry, as (R)- or (S)- or,as (D)- or (L)- for amino acids. Embodiments thus include all suchpossible isomers, as well as their racemic and optically pure forms.Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers maybe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, for example, chromatography and fractionalcrystallization. Conventional techniques for the preparation/isolationof individual enantiomers include chiral synthesis from a suitableoptically pure precursor or resolution of the racemate (or the racemateof a salt or derivative) using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms are alsoincluded.

Although pharmaceutically unacceptable salts are not generally useful asmedicaments, such salts may be useful, for example as intermediates inthe synthesis of compounds having structure (I), for example in theirpurification by recrystallization.

As used herein, the phrase “MRGPRX2 dependent condition” means acondition where the activation, over sensitization, or desensitizationof MRGPRX2 by a natural or synthetic ligand initiates, mediates,sustains, or augments a pathological condition. For example, it is knownthat some cationic peptidergic drugs cause pseudo-allergic reactions inpatients MRGPRX2 is sensitive to (or activated by) secretagogues,cationic peptidergic drugs, including icatibant, leuprolide, organirelix, neutral and anionic peptidergic drugs (e.g., exenatide,glucagon, liraglutide, enfuviritide, colistimethate), non-steroidalagonist (atracurium mivacurium), non-steroidal antagonist drugs,neuropeptides, and antimicrobial peptides. Moreover, overexpression ofMRGPRX2 and/or overactivity of MRGPRX2 may also render mast cells moresusceptible to activation by endogenous and/or exogenous ligands.Without limited by theory, it is to be understood that by modulatingMRGPRX2, pseudo-allergic reactions, itch, pain, inflammatory orautoimmune disorders can be eased.

In some embodiments, the MRGPRX2 dependent condition is a condition thatis caused by IgE independent activation of MRGPRX2. IgE independentactivation of MRGPRX2 is capable of inducing mast cell degranulation.For example, IgE independent mast cell activation associated with somecases of chronic urticaria and other mast cell mediated conditions,which are not responsive to current anti-IgE or antihistamine therapies.Thus, the compounds of the present disclosure may be used for treatingan MRGPRX2 dependent condition caused by IgE independent activation ofMRGPRX2 and that would benefit from modulating MRGPRX2.

In some embodiments, the MRGPRX2 dependent condition is an itchassociated condition, a pain associated condition, a pseudo-allergicreaction, an autoimmune or inflammatory disorder, or cancer-associatedcondition.

As used herein the phrase “pseudo-allergic reaction” refers to anIgE-independent allergic reaction, characterized by histamine release,inflammation, airway contraction, or any combination thereof. Apseudo-allergic reaction may be an analphylactic reaction. Apseudo-allergic reaction may be caused by a range of cationicsubstances, collectively called basic secretagogues, includinginflammatory peptides and drugs associated with allergic-type reactions.Thus, in one embodiment, the method of present invention is provided totreat a pseudo-allergic reaction, such as pseudo-allergic reactionscaused by secretagogues, cationic peptidergic drugs, anionic peptidergicdrugs, neutral peptidergic drugs, non-steroidal antagonist drugs,neuropeptides, and antimicrobial peptides. In one embodiment, thepseudo-allergic reaction is caused by MCD peptide, Substance P, VIP,PACAP, dynorphin, somatostatin, Compound 48/80, cortistatin-14,mastoparan, melettin, cathelicidin peptides, ciprofloxacin, vancomycin,leuprolide, goserelin, histrelin, triptorelin, cetrorelix, ganirelix,degarelix, octreotide, lanreotide, pasireotide, sermorelin, tesamorelin,icatibant, glatiramer acetate, teriparatide, pramlintide, bleomycin,exenatide, glucagon, liraglutide, enfuvirtide, colistimethate,succinylcholine, tubocurarine, atracurium, mivacurium, and rocuronium.

As used herein, the phrase “itch associated condition” means pruritus(including acute and chronic pruritus) associated with any condition.The itch sensation can originate, e.g., from the peripheral nervoussystem (e.g., dermal or neuropathic itch) or from the central nervoussystem (e.g., neuropathic, neurogenic or psychogenic itch). Thus, in oneembodiment, the method of present invention is provided to treat an itchassociated condition, such as chronic itch; contact dermatitis; Allergicblepharitis; Anaphylaxis; Anaphylactoid drug reactions; Anaphylacticshock; Anemia; Atopic dermatitis; Bullous pemphigoid; Candidiasis;Chicken pox; end-stage renal failure; hemodialysis; Cholestaticpruritis; Chronic urticaria; Contact dermatitis, Dermatitisherpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis;Ectopic eczema; Eosinophilic fasciitis; Epidermolysis bullosa;Erythrasma; Food allergy; Folliculitis; Fungal skin infection;Hemorrhoids; Herpes; HIV infection; Hodgkin's disease; Hyperthyroidism;Iodinated contrast dye allergy; Iron deficiency anemia; Kidney disease;Leukemia, porphyrias; Lymphoma; Mast cell activation syndrome,Malignancy; Mastocystosis; Multiple myeloma; Neurodermatitis;Onchocerciasis; Paget's disease; Pediculosis; Polycythemia rubra vera;Prurigo nodularis; Lichen Planus; Lichen Sclerosis; Pruritus ani;Pseudo-allergic reactions; Pseudorabies; Psoriasis; Rectal prolapse;Sarcoidosis granulomas; Scabies; Schistosomiasis; Scleroderma, Severestress, Stasia dermatitis; Swimmer's itch; Thyroid disease; Tineacruris; Uremic Pruritus; Rosacea; Cutaneous amyloidosis; Scleroderma;Acne; wound healing; burn healing; ocular itch; and Urticaria.

As used herein, the phrase “pain associated condition” means any paindue to a medical condition. Thus, in one embodiment, the method ofpresent invention is provided to treat a pain associated condition, suchas Acute Pain, Advanced Prostate Cancer, AIDS-Related Pain, AnkylosingSpondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic CerebralPalsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain,Behcet's Disease (Syndrome), Burning Mouth Syndrome, Bursitis, CancerPain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome,Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease,Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain(CFAP), Chronic Pain, Chronic Pancreatitis, Chronic Pelvic PainSyndrome, Collapsed Lung (Pneumothorax), Complex Regional Pain Syndrome(RSD), Corneal Neuropathic Pain, Crohn's Disease, Degenerative DiscDisease, Dental Pain, Dercum's Disease, Dermatomyositis, DiabeticPeripheral Neuropathy (DPN), Dystonia, Ehlers-Danlos Syndrome (EDS),Endometriosis, Eosinophilia-Myalgia Syndrome (EMS), Erythromelalgia,Fibromyalgia, Gout, Headaches, Herniated disc, Hydrocephalus,Intercostal Neuraligia, Interstitial Cystitis, Irritable Bowel syndrome(IBS), Juvenile Dermatositis (Dermatomyositis), Knee Injury, Leg Pain,Loin Pain-Haematuria Syndrome, Lupus, Lyme Disease, Medullary SpongeKidney (MSK), Meralgia Paresthetica, Mesothelioma, Migraine,Musculoskeletal pain, Myofascial Pain, Myositis, Neck Pain, NeuropathicPain, Occipital Neuralgia, Osteoarthritis, Paget's Disease, ParsonageTurner Syndrome, Pelvic Pain, Periodontitis Pain, Peripheral Neuropathy,Phantom Limb Pain, Pinched Nerve, Polycystic Kidney Disease, PolymyalgiaRhuematica, Polymyositis, Porphyria, Post Herniorraphy Pain Syndrome,Post Mastectomy, Postoperative Pain, Pain Syndrome, Post Stroke Pain,Post Thorocotomy Pain Syndrome, Postherpetic Neuralgia (Shingles),Post-Polio Syndrome, Primary Lateral Sclerosis, Psoriatic Arthritis,Pudendal Neuralgia, Radiculopathy, Raynaud's Disease, RheumatoidArthritis (RA), Sacroiliac Joint Dysfunction, Sarcoidosi, Scheuemann'sKyphosis Disease, Sciatica, Scoliosis, Shingles (Herpes Zoster),Sjogren's Syndrome, Spasmodic Torticollis, Sphincter of OddiDysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal Cord Injury,Spinal Stenosis, Syringomyelia, Tarlov Cysts, Transverse Myelitis,Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis, VascularPain and Vulvodynia.

As used herein, the term “autoimmune disorder”, or “inflammatorydisorder” means a disease or disorder arising from and/or directedagainst an individual's own tissues or organs, or a co-segregate ormanifestation thereof, or resulting condition therefrom. Typically,various clinical and laboratory markers of autoimmune diseases may existincluding, but not limited to, hypergammaglobulinemia, high levels ofautoantibodies, antigen-antibody complex deposits in tissues, clinicalbenefit from corticosteroid or immunosuppressive treatments, andlymphoid cell aggregates in affected tissues. Thus, in one embodiment,the method of present invention is provided to treat an autoimmunedisorder, such as chronic inflammation, mast cell activation syndrome,Multiple Sclerosis, Steven Johnson's Syndrome, Toxic EpidermalNecrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis,dermatitis, phlebitis, reflex sympathetic dystrophy/complex regionalpain syndrome (rsd/crps), rhinitis, tendonitis, tonsillitis, acnevulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease,reactive airway disorder, asthma, airway infection, allergic rhinitis,autoinflammatory disease, celiac disease, chronic prostatitis,diverticulitis, glomerulonephritis, hidradenitis suppurativa,hypersensitivities, intestinal disorder, epithelial intestinal disorder,inflammatory bowel disease, irritable bowel syndrome, Crohn's Disease,ulcerative colitis, lupus erythematous, interstitial cystitis, otitis,pelvic inflammatory disease, endometrial pain, reperfusion injury,rheumatic fever, rheumatoid arthritis, sarcoidosis, transplantrejection, psoriasis, lung inflammation, chronic obstructive pulmonarydisease, permanent sputum eosiniophilia, eosinophilic leukemia,eosinophilic esophagitis, eosinophilic gastritis, eosinophilicduodenitis, eosinophilic gastroenteritis, mast cell gastrointestinaldisease, hypereosinophilic syndrome, aspirin-exacerbated respiratorydisease, nasal polyposis, chronic rhinosinusitis, antibody-dependentcell-mediated cytotoxicity, neurofibromatosis, swannamatoisis,tubulointerstitial nephritis, glomerulonephritis, diabetic nephropathy,allograft rejection, amyloidosis, renovascular ischemia, refluxnephropathy, polycystic kidney disease, liver fibrosis/cirrhosis,autoimmune liver disease, Biliary atresia, acute and chronic Hepatitis Band C virus, Liver tumors and cancer, Alcoholic liver disease,Polycystic liver disease, Liver cholangiocarcinoma, neuromyelitis opticaspectum disorder, cardiovascular disease, inflammation induced bybacterial or viral infection, inflammation associated with SARS-CoV-2infection or its variants and Coronavirus Disease 2019 (COVID-19), acuterespiratory distress syndrome, pneumonia, Long/Long-Term/Chronic COVID,Post-Acute Sequelae of COVID-19 (PASC), myalgicencephalomyelitis/chronic fatigue syndrome (ME/CFS “Brain Fog”) andvasculitis.

As used herein the phrase “cancer associated condition” means anydisease arising from the proliferation of malignant cancerous cells.Thus, in one embodiment, the method of present invention is provided totreat a cancer/tumor associated condition, such as adenoid cysticcarcinoma, adrenal gland tumor, amyloidosis, anal cancer, appendixcancer, astrocytoma, ataxia-telangiectasia, beckwith-wiedemann syndrome,cholangiocarcinoma, birt-hogg-dube syndrome, bone cancer, brain stemglioma, brain tumor, breast cancer (inflammatory, metastatic, male),prostrate, basal cell, melanoma, colon, colorectal, bladder, kidneycancer, lacrimal gland cancer, laryngeal and hypopharyngeal cancer, lungcancer (non-small cell, small cell), leukemia (acute lymphoblastic,acute lymphocytic, acute myeloid, B cell prolymphocytic, chroniclymphocytic, chronic myeloid, chronic T cell lymphocytic, eosinophilic),Liver Cancer, Li-Fraumei syndrome, lymphoma (Hodgkin and non-hodgkin),lynch syndrome, mastocytosis, medulloblastoma, meningioma, mesothelioma,multiple endocrine neoplasia, multiple myeloma, MUTYH-associatedpolyposis, myelodyspastic syndrome, nasal cavity and paranasal sinuscancer, neurobastoma, neuroendocrine tyymors, neurofibromatosis, penilecancer, parathyroid cancer, ovarian fallopian tube and peritonealcancer, osteosarcoma, pituitary gland tumor, pleupulmonary blastoma,oral and oropharyngeal, thyroid, uterine, pancreatic, carney complex,brain and spinal cord cancer, cervical cancer, cowden syndrome,craniopharyngioma, desmoid tumor, desmoplatic infantile ganglioglioma,ependymoma, esophageal cancer, ewing sarcoma, eye cancer, eyelid cancer,familial adenomatous polyposis, familial GIST, familial malignantmelanoma, familial pancreatic cancer, gallbladder cancer,gastrointestinal stromal tumor, germ cell tumor, gestationaltrophoblastic disease, head and neck cancer, hereditary breast andovarian cancer, hereditary diffuse gastric cancer, hereditary,leiomyomastosis and renal cell cancer, hereditary pancreatitis,herediatary papillary renal carcinoma, hereditary mixed polyposissyndrome, HIV/AIDS related cancers, retinoblastoma, rhabdomyosarcoma,salivary glanc cancer, Kaposi sarcoma, small bowel cancer, stomachcancer, testicular cancer, thymoma and thymic carcinoma, thyroid cancer,vaginal cancer, culver cancer, werner syndrome and Xerodermapigmentosum.

As used herein, the term “administration” refers to providing acompound, or a pharmaceutical composition comprising the compound asdescribed herein. The compound or composition can be administered byanother person to the subject or it can be self-administered by thesubject. Non-limiting examples of routes of administration are oral,parenteral (e.g., intravenous), or topical.

As used herein, the term “treatment” refers to an intervention thatameliorates a sign or symptom of a disease or pathological condition. Asused herein, the terms “treatment”, “treat” and “treating,” withreference to a disease, pathological condition or symptom, also refersto any observable beneficial effect of the treatment. The beneficialeffect can be evidenced, for example, by a delayed onset of clinicalsymptoms of the disease in a susceptible subject, a reduction inseverity of some or all clinical symptoms of the disease, a slowerprogression of the disease, a reduction in the number of relapses of thedisease, an improvement in the overall health or well-being of thesubject, or by other parameters well known in the art that are specificto the particular disease. A prophylactic treatment is a treatmentadministered to a subject who does not exhibit signs of a disease orexhibits only early signs, for the purpose of decreasing the risk ofdeveloping pathology. A therapeutic treatment is a treatmentadministered to a subject after signs and symptoms of the disease havedeveloped.

As used herein, the term “subject” refers to an animal (e.g., a mammal,such as a human). A subject to be treated according to the methodsdescribed herein may be one who has been diagnosed with a MRGPRX2 orMRGPRX2 ortholog B2 dependent condition, such as a pseudo-allergicreaction, an itch associated condition, a pain associated condition,inflammatory or an autoimmune disorder. Diagnosis may be performed byany method or technique known in the art. One skilled in the art willunderstand that a subject to be treated according to the presentdisclosure may have been subjected to standard tests or may have beenidentified, without examination, as one at risk due to the presence ofone or more risk factors associated with the disease or condition. Theterm “patient” may be used interchangeably with the term “subject.” Asubject may refer to an adult or pediatric subject.

The Federal Food, Drug, and Cosmetic Act defines “pediatric” as asubject aged 21 or younger at the time of their diagnosis or treatment.Pediatric subpopulations are further characterized as: (i) neonates—frombirth through the first 28 days of life; (ii) infants—from 29 days toless than 2 years; (iii) children—2 years to less than 12 years; and(iv) adolescents—aged 12 through 21. Despite the definition, dependingon the susceptible patient population and clinical trial evaluation, anapproved regulatory label may include phrasing that specificallymodifies the range of a pediatric population, such as, for example,pediatric patients up to 22 years of age.

In another embodiment, the method of treating a subject having a MRGPRX2dependent condition (e.g., an itch associated condition, a painassociated condition, a pseudo-allergic reaction, or an inflammatory orautoimmune disorder) described herein further comprises administering tothe subject a pharmaceutically effective amount of a second therapeuticagent. In one embodiment, the itch associated condition is apseudo-allergic condition.

In one embodiment, the second therapeutic agent is an antihistamine,such as an H1 receptor antagonist or an H2 receptor antagonist. In oneembodiment, the second therapeutic agent is an H1 receptor antagonistantihistamine, such as levocetirizine, loratadine, fexofenadine,cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadineor hydroxyzine pamoate. In one embodiment, the second therapeutic agentis a H2 receptor antagonist, such as cimetidine, nizatidine, ranitidineor famotidine. In one embodiment, the second therapeutic agent is aleukotriene receptor antagonist or leukotriene synthesis inhibitor, suchas montelukast, zafirlukast, pranlukast, or 5-lipoxygenase inhibitor(e.g., zileuton, hypericum perforatum). In one embodiment, the secondtherapeutic agent is an immunomodulatory agent such as Omalizumab orimmunoglobulin therapy. In one embodiment, the second therapeutic agentis a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb,triamcinolone, prednisone, prednisolone, or fludrocortisone. In oneembodiment, the second therapeutic agent is a tricylic antidepressantthat can relieve itch such as doxepin, amitriptyline or nortriptyline.In one embodiment, the second therapeutic agent is an anti-inflammatorydrug such as dapsone, sulfasalazine, hydroxycholoroquine or colchicine.In one embodiment, the second therapeutic agent is an immunosuppressantsuch as cyclosporine, methotrexate, mycophenolic acid or tacromilus.

The second therapeutic agent may be administered simultaneously,separately, or sequentially with the compounds of the presentdisclosure. If administered simultaneously, the second therapeutic agentand compound of the present disclosure may be administered in separatedosage forms or in the same dosage form.

In another embodiment, a method of treating a subject having an itchassociated condition is provided, the method comprising administering tothe subject a pharmaceutically effective amount of a compound havingstructure (I) or a pharmaceutically acceptable salt, isomer, hydrate,solvate or isotope thereof, or a pharmaceutical composition thereof. Inone embodiment, the itch associated condition is urticaria, pruritus,atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.In another embodiment, a method of treating a subject having aninflammation or autoimmune associated condition is provided, the methodcomprising administering to the subject a pharmaceutically effectiveamount of a compound having structure (I) or a pharmaceuticallyacceptable salt, isomer, hydrate, solvate or isotope thereof, or apharmaceutical composition thereof. In one embodiment, the inflammationor autoimmune associated condition is sinusitis, asthma, rosacea, orendometriosis.

In another embodiment, a method of treating a subject having a painassociated condition is provided, the method comprising administering tothe subject a pharmaceutically effective amount of a compound havingstructure (I) or a pharmaceutically acceptable salt, isomer, hydrate,solvate or isotope thereof, or a pharmaceutical composition thereof. Inone embodiment, the pain associated condition is chronic pelvic painsyndrome, endometriosis pain, fibromyalgia, migraine or postoperativepain.

Compounds

As detailed above, the present disclosure provides compounds showingsignificant activity as MRGPRX2 antagonists. Accordingly, one embodimentprovides a compound having the following structure (I):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof,wherein:

-   -   R¹ is cycloalkyl, aryl, heterocyclyl, —(CH₂)_(n)Q, —CHQR, or        —CQ(R)₂, wherein R¹ is optionally substituted with one or more        R^(q1);    -   Q is C₁₋₆ alkyl, aryl, cycloalkyl, heterocyclyl, —CH₂C(O)OR,        —C(O)OR, —C(O)NHR, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R,        —N(R)C(O)OR, or —N(R)S(O)₂R, wherein Q is optionally substituted        with one or more R^(q2);    -   R^(q1) and R^(q2) are independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR,        —O(CH₂)_(n)R, haloalkoxy, —C(O)OR, —C(O)R, —OC(O)R, halo,        haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, S(O)₂R,        —C(H)Q′R, or —(CH₂)_(n)Q′ where Q′ is selected from C₁₋₆ alkyl,        aryl, cycloalkyl, heterocyclyl, OR′, —C(O)OR′, —OC(O)R′,        haloalkyl, —CN, —N(R′)₂, —N(R′)C(O)R′, and —N(R′)S(O)₂R′;    -   A is N or CR^(a);    -   B is N or CR^(b);    -   C is N or CR^(c);    -   D is CR^(d);    -   E is N or CR^(e);    -   G is N or CR^(g);    -   W is CR^(w);    -   Y is N, S or CR^(y);    -   Z is N, CR^(z), S or O;    -   each R is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, alkylamino, —(CH₂)_(n)R′, halo, aryl, cycloalkyl,        heteroaryl or heterocyclyl, or two R groups taken together with        the atom to which they are attached form a carbocyle or        heterocycle;        -   R′ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, haloalkyl,            aryl, cycloalkyl, heteroaryl, or heterocyclyl;    -   R^(a) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R,        halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or        S(O)₂R;    -   R^(b) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R,        halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or        S(O)₂R;    -   R^(c) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R,        halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or        S(O)₂R;    -   R^(d) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN,        —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R;    -   R^(e) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN,        —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R;    -   R^(g) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN,        —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R;    -   R^(w) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN,        —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R;    -   R^(y) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R,        halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or        S(O)₂R;    -   R^(z) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R,        halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or        S(O)₂R;    -   n is independently 0, 1, 2, 3, 4 and 5;    -   R⁶ is C₁₋₄ alkyl, phenyl, —C(O)R, —(CH₂)_(n)OR, —CN, F, Cl, Br,        CF₃, CF₂H or CFH₂, with the proviso that R is not H;    -   each R⁸ is independently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR,        —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R,        —N(R)S(O)₂R, or S(O)₂R;    -   R², R³, R⁴, R⁵ and R⁷ are the same or different and either        absent or, when present, independently H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, —CN, —N(R)₂,        —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R;    -   wherein:    -   adjacent atoms on either the “a” ring or “b” ring may be joined        together by single bonds to form a 9 atom carbocyclic or        heterocyclic ring structure; or    -   atoms 1 and 2, 3 and 4, 5 and 6 and 8 and 9 on rings “a” ring        and “b” ring may be joined together by double bonds to form an        aromatic 9 atom carbocyclic or heterocyclic ring structure; or    -   atoms 1 and 2, 3 and 4, 6 and 7 and 8 and 9 on rings “a” ring        and “b” ring may be joined together by double bonds to form an        aromatic 9 atom carbocyclic or heterocyclic ring structure;    -   with the provisos that:        -   when Z is S or N, then A and C cannot both be N; and        -   when Z is N, then C and G cannot both be N.

In another embodiment, compounds are provided of the followingstructures (Ia) or (Ia′):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof.

In yet another embodiment, compounds are provided of the followingstructures (Ib), (Ic) or (Id):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof.

In one embodiment R¹ is aryl, —(CH₂)_(n)Q, —CHQR, or —CQ(R)₂, wherein R¹is optionally substituted with one or more R^(q1);

-   -   Q is aryl, —CH₂C(O)OR, —C(O)OR, —C(O)NHR, haloalkyl, —CN,        —N(R)₂, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)S(O)₂R, wherein Q is        optionally substituted with one or more R^(q2).

In another embodiment, R¹ is phenyl.

In some embodiments, the aryl is unsubstituted.

In yet another embodiment, the aryl is substituted with one or moreR^(q1). In yet other embodiments, R^(q1) is H, —OR, —N(R)S(O)₂R, —CN,—N(R)C(O)R or —C(H)Q′R.

In one embodiment, R¹ is heterocyclyl, —(CH₂)_(n)Q, —CHQR, or —CQ(R)₂,wherein R¹ is optionally substituted with one or more R^(q1);

-   -   Q is heterocyclyl, —CH₂C(O)OR, —C(O)OR, —C(O)NHR, haloalkyl,        —CN, —N(R)₂, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)S(O)₂R, wherein Q        is optionally substituted with one or more R^(q2).

In some embodiments, the heterocyclyl is unsubstituted.

In yet another embodiment, the heterocyclyl is substituted with one ormore R^(q1). In some embodiments, R^(q1) is H or C₁₋₆ alkyl.

In one embodiment, R⁶ is CF₃, CF₂H, CFH₂, C₁₋₆ alkyl, —C(O)R,—(CH₂)_(n)OR or —CN.

In another embodiment, R⁶ is CF₃.

In yet another embodiment, R⁶ is CF₂H.

In some embodiments, R⁶ is C₁₋₆ alkyl.

In one embodiment, R⁶ is —C(O)R. In other embodiments, R is C₁₋₆ alkyl.

In one embodiment, R⁶ is —(CH₂)_(n)OR. In another embodiment, n is 0. Inyet another embodiment, n is 1. In yet other embodiments, R is C₁₋₆alkyl.

In one embodiment, R⁶ is —CN.

In other embodiments, each R⁸ is H.

In one embodiment, Z is N or S.

In some embodiments, each of A, B, C, and Y are CH.

In one embodiment, E is N.

In some embodiments, R^(w) is absent.

In one embodiment, atoms 1 and 2, 3 and 4, 5 and 6 and 8 and 9 on rings“a” ring and “b” ring are joined together by double bonds to form anaromatic 9 atom heterocyclic ring structure.

In other embodiments, atoms 1 and 2, 3 and 4, 6 and 7 and 8 and 9 onrings “a” ring and “b” ring are joined together by double bonds to forman aromatic 9 atom heterocyclic ring structure.

In one embodiment, a compound is selected from any one of compoundslisted in Table I, or a pharmaceutically acceptable salt, isomer,hydrate, solvate or isotope thereof.

TABLE 1 Representative compounds having Structure (I) Cpd Structure No.

1-1 

1-2 

1-3 

1-4 

1-5 

1-6 

1-7 

1-8 

1-9 

1-10

1-11

1-12

1-13

1-14

1-15

1-16

1-17

1-18

1-19

1-20

1-21

1-22

1-23

1-24

1-25

1-26

1-27

1-28

1-29

1-30

1-31

1-32

1-33

1-34

1-35

1-36

1-37

1-38

1-39

1-40

1-41

1-42

1-43

1-44

2-1 

2-2 

2-3 

2-4 

2-5 

2-6 

2-7 

2-8 

2-9 

2-10

2-11

2-12

2-13

2-14

2-15

2-16

2-17

2-18

2-19

2-20

2-21

2-22

2-23

2-24

2-25

2-26

2-27

2-28

2-29

2-30

2-31

2-32

2-33

2-34

2-35

2-36

2-37

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2-111

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2-113

2-114

2-115

2-116

2-117

2-118

2-119

2-120

2-121

2-122

2-123

2-124

2-125

2-126

2-127

2-128

2-129

2-130

2-131

2-132

2-133

2-134

2-135

2-136

2-137

2-138

2-139

2-140

2-141

2-142

2-143

2-144

2-145

2-146

2-147

2-148

2-149

2-150

2-151

2-152

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2-159

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2-163

2-164

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2-168

2-169

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2-171

2-172

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2-297

Representative compounds of structure (I), as well as structures (Ia),(Ia′), (Ib), (Ic) or (Id) as applicable, include, but not limited to,any one of the compounds listed below in their IUPAC names as well as apharmaceutically acceptable salt, isomer, hydrate, solvate or isotopethereof.

-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)-1,3-benzothiazol-4-yl]amino}cyclohexyl]benzamide;-   N-[(1R,3S)-3-{[2-(ethoxymethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]-4-methoxybenzamide;-   N-[(1R,3S)-3-[(2-acetyl-1-benzothiophen-4-yl)amino]cyclohexyl]-4-methoxybenzamide;-   4-fluoro-N-[(1s,4s)-4-[(2-acetyl-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(ethoxymethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[1-methyl-2-(trifluoromethyl)-1H-indol-4-yl]amino}cyclohexyl]benzamide;-   N-[(1R,3S)-3-{[2-(difluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]-4-methoxybenzamide;-   N-[(1R,3S)-3-[(2-ethyl-1-benzothiophen-4-yl)amino]cyclohexyl]-4-methoxybenzamide;-   4-methoxy-N-[(1R,3S)-3-[(2-methyl-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-[(2-methyl-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-[(2-ethyl-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(difluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-[(2-methoxy-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-[(2-methoxy-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   N-[(1R,3S)-3-[(2-cyano-1-benzothiophen-4-yl)amino]cyclohexyl]-4-methoxybenzamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1,3-benzothiazol-4-yl]amino}cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-7-yl]amino}cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1,3-benzothiazol-7-yl]amino}cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-[(2-cyano-1-benzothiophen-4-yl)amino]cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide;-   3-acetamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   1-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]-1,2,3,4-tetrahydroquinoline-6-carboxamide;-   3-(1-cyanoethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   3-methanesulfonamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-6-carboxamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)-1-benzothiophen-7-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)-1,3-benzoxazol-4-yl]amino}cyclohexyl]benzamide;-   3-cyano-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1-benzothiophen-4-yl]amino}cyclohexyl]benzamide;-   2-amino-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-thiazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-6-carboxamide;-   4-(N-methylmethanesulfonamido)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-(dimethylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-4-carboxamide;-   4-(dimethylamino)-2-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-(morpholin-4-yl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-(dimethylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-(propane-2-sulfonamido)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-3-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-(1H-1,2,3,4-tetrazol-1-yl)benzamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-({2-phenylimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   3-(propane-2-sulfonamido)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)-2H-indazol-4-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-cyano-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-(methylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   2-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   2-amino-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrimidine-5-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]-4-sulfamoylbenzamide;-   4-methanesulfonyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]-2H-1,2,3-triazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,2,3-triazole-4-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl]amino}cyclohexyl]benzamide;-   3-cyano-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-(methylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-methanesulfonamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-cyano-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-(methylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methanesulfonamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridazine-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   4-(4-methylpiperazin-1-yl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-chloro-4-methanesulfonyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-chloro-4-(propan-2-yloxy)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   6-(methylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-2-carboxamide;-   3-(1-cyanoethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-acetamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-acetamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   4-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   methyl    4-{[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]carbamoyl)benzoate;-   4-acetamido-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-3-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-7-carboxamide;-   2-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-3-carboxamide;-   5-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-6-carboxamide;-   5,7-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-(4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl)imidazo[1,5-a]pyridine-7-carboxamide;-   2-methyl-N-(4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;-   N-(4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-imidazole-5-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,2,3-triazole-5-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-(4H-1,2,4-triazol-4-yl)benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,5-a]pyridine-6-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-7-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-6-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-5-carboxamide;-   6-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-b]pyridazine-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4H,5H,6H,7H-pyrazolo[1,5-a]pyridine-2-carboxamide;-   7-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide;-   5-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-imidazo[4,5-b]pyridine-7-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-3-carboxamide;-   2,3-dioxo-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2,3-dihydro-1H-indole-7-carboxamide;-   2-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-benzothiazole-4-carboxamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-3-carboxamide;-   1,5-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-3-carboxamide;-   1-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,2-oxazole-5-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrole-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;-   2-hydroxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   2-(dimethylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-a]pyrazine-2-carboxamide;-   6-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]quinoline-8-carboxamide;-   6-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-chromene-3-carboxamide;-   5-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   6-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-benzothiophene-2-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-6-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[3,2-c]pyridine-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-pyrazolo[4,3-b]pyridine-7-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-a]pyrimidine-3-carboxamide;-   1,3-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   1-(propan-2-yl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   1-phenyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-pyrazolo[4,3-c]pyridine-7-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1,3-benzothiazol-7-yl]amino}cyclohexyl]benzamide;-   2-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   6-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   2,6-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[7-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)-1,3-benzoxazol-7-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[3-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[7-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-imidazole-5-carboxamide;-   3-methoxy-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   3-methoxy-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-cyano-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-amino-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-(difluoromethyl)-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]aminocyclohexyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide;-   3-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]benzamide;-   4-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-ethoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   2-(propan-2-yloxy)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   4-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]benzamide;-   2-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-7-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-pyrazolo[3,4-b]pyridine-4-carboxamide;-   4-chloro-3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   5-(methylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   2-[(propan-2-yl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-c]pyridine-4-carboxamide;-   2-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrimidine-5-carboxamide;-   1,2-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-imidazole-5-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,2-oxazole-5-carboxamide;-   4-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,2-oxazole-5-carboxamide;-   1-ethyl-3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   1-ethyl-3-(propan-2-yl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   methyl    1-ethyl-5-{[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazole-3-carboxylate;-   methyl    1-ethyl-3-{[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]carbamoyl}-1H-pyrazole-5-carboxylate;-   1-(2,2-difluoroethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-(propan-2-yl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-(difluoromethyl)-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   5-cyclopropyl-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   3-chloro-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-amino-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,2-thiazole-4-carboxamide;-   5-amino-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-cyano-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-ethyl-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2-[(2,2,2-trifluoroethyl)amino]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-3-[(2,2,2-trifluoroethyl)amino]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-[(2,2,2-trifluoroethyl)amino]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-benzoxazole-7-carboxamide;-   2-(ethylamino)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   1,3-diethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   1,5-diethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-3-carboxamide;-   5-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[8-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,2-benzothiazole-7-carboxamide;-   3-(difluoromethyl)-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   5-cyclopropyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1R,3S)-3-{[7-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1R,3S)-3-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-methoxybenzamide;-   N-[(1R,3S)-3-{[6-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-methoxybenzamide;-   4-methoxy-N-[(1R,3S)-3-{[8-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1R,3S)-3-{[7-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-methoxybenzamide;-   N-[(1R,3S)-3-{[8-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-methoxybenzamide;-   N-[(1R,3S)-3-{[8-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-methoxybenzamide;-   6-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   3-amino-1-(2,2-difluoroethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-amino-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;-   N-[(1R,3S)-3-{[7-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-methoxybenzamide;-   1-(2,2-difluoroethyl)-3-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;-   1-(2,2-difluoroethyl)-5-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-(2-fluoroethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-(2,2-difluoroethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[7-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[3-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-cyclopropyl-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   2-chloro-4-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-pyrazolo[4,3-b]pyridine-7-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-(dimethylamino)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-(difluoromethyl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-benzothiazole-7-carboxamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-7-carboxamide;-   3-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-7-carboxamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide;-   1,3-dimethyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   2,4-dichloro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2-[(2,2,2-trifluoroethyl)amino]benzamide;-   2-(methylamino)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-chloro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-chloro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4-carboxamide;-   5-fluoro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-benzofuran-2-carboxamide;-   3-chloro-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-(difluoromethyl)-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   3-ethyl-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-[(2,2-difluoroethyl)amino]-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrole-3-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-5-carboxamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,3-thiazole-5-carboxamide;-   6-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   2-amino-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   6-ethyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   6-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   4-(2-fluoroethoxy)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-chloro-4-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-chloro-4-fluoro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-pyrazolo[4,3-b]pyridine-7-carboxamide;-   5-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   6-fluoro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   1-propyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-(propan-2-yl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   4-methoxy-3-(methylamino)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-chloro-1-(2-fluoro-2-methylpropyl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   4-(dimethylamino)-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   4-(methylamino)-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   3-methoxy-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   4-fluoro-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   2-(methylamino)-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   4-methyl-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   3-chloro-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   4-chloro-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   3-methyl-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]benzamide;-   3-methyl-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]-2H-indazole-7-carboxamide;-   5-fluoro-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]-1-benzofuran-2-carboxamide;-   1,3-dimethyl-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]-1H-pyrazole-4-carboxamide;-   1-(2,2-difluoroethyl)-3-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   6-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-3-carboxamide;-   4-(methylamino)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   1,4-dimethyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrole-3-carboxamide;-   1,3-bis(difluoromethyl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-(2-hydroxy-2-methylpropyl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-methyl-N-[(1s,4s)-4-({2-cyanoimidazo[1,2-a]pyridin-5-yl}amino)cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-(difluoromethyl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   5-fluoro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide;-   1-(difluoromethyl)-5-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrole-3-carboxamide;-   2-[(2-fluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-[(2-fluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-4-[(2,2,2-trifluoroethyl)amino]benzamide;-   4-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   6-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-2-carboxamide;-   2-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyridine-4-carboxamide;-   2-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-imidazo[4,5-b]pyridine-7-carboxamide;-   3-cyano-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]imidazo[1,2-a]pyridine-6-carboxamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide;-   3-fluoro-4-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2,4-dimethoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3,4-dimethoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-[(2-fluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   3-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-(difluoromethyl)-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-7-carboxamide;-   3-[(2,2-difluoroethyl)amino]-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]pyrazolo[1,5-a]pyridine-2-carboxamide;-   1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-3-carboxamide;-   5-[(2,2-difluoroethyl)amino]-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino)cyclohexyl]-1H-pyrazole-4-carboxamide;-   2-fluoro-4-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   1,2-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-3-carboxamide;-   2-chloro-4-[(2,2-difluoroethyl)(methyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   2-chloro-4-[methyl(2,2,2-trifluoroethyl)amino]-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-methoxy-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2-[(2,2,2-trifluoroethyl)amino]benzamide;-   N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]quinoline-8-carboxamide;-   3-(3,3-difluoropropyl)-1-methyl-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   1,3-bis(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-cyano-1-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   2,2,3,3-tetramethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]cyclopropane-1-carboxamide;-   2-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-7-carboxamide;-   1-methyl-N-(4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl)-1H-indole-3-carboxamide;-   N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1,2-benzoxazole-3-carboxamide;-   1,2-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-4-carboxamide;-   1,2-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-4-carboxamide;-   3-chloro-N-[(1s,4s)-4-{[2-(difluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   3-chloro-1-(difluoromethyl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   4-methoxy-N-[(1s,4s)-4-{[8-fluoro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;-   4-chloro-1-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-indole-3-carboxamide;-   5-chloro-1-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-ethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   3-chloro-1-(propan-2-yl)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrazole-4-carboxamide;-   2-methyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-1,3-benzodiazole-7-carboxamide;-   3-fluoro-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-2H-indazole-7-carboxamide;-   4-(2-fluoroethoxy)-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]benzamide;    and-   1,5-dimethyl-N-[(1s,4s)-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino}cyclohexyl]-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.

Pharmaceutical Compositions

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising a compound of structure (I) or any of thestructures (Ia), (Ia′), (Ib), (Ic) or (Id), or a pharmaceuticallyacceptable salt, isomer, hydrate, solvate or isotope thereof, togetherwith at least one pharmaceutically acceptable carrier, diluent, orexcipient. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

As used herein, the term “pharmaceutical composition” refers to acomposition containing one or more of the compounds described herein, ora pharmaceutically acceptable isomer, racemate, hydrate, solvate,isotope or salt thereof, formulated with a pharmaceutically acceptablecarrier, which can also include other additives, and manufactured orsold with the approval of a governmental regulatory agency as part of atherapeutic regimen for the treatment of disease in a mammal.Pharmaceutical compositions can be formulated, for example, for oraladministration in unit dosage form (e.g., a tablet, capsule, caplet,gelcap, or syrup); for topical administration (e.g., as a cream, gel,lotion, or ointment); for intravenous administration (e.g., as a sterilesolution free of particulate emboli and in a solvent system suitable forintravenous use); for administration to a pediatric subject (e.g.,solution, syrup, suspension, elixir, powder for reconstitution assuspension or solution, dispersible/effervescent tablet, chewabletablet, lollipop, freezer pops, troches, oral thin strips, orallydisintegrating tablet, orally disintegrating strip, and sprinkle oralpowder or granules); or in any other formulation described herein.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed.,Lippencott Williams & Wilkins (2005) and in The United StatesPharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

In some embodiments, the pharmaceutical composition comprising acompound of structure (I) or any of the structures (Ia), (Ia′), (Ib),(Ic) or (Id), or a pharmaceutically acceptable salt, isomer, hydrate,solvate or isotope thereof, with at least one pharmaceuticallyacceptable carrier, diluent, or excipient further comprises a secondtherapeutic agent.

In one embodiment, the second therapeutic agent is an antihistamine,such as an H1 receptor antagonist or an H2 receptor antagonist. In oneembodiment, the second therapeutic agent is an H1 receptor antagonistantihistamine, such as levocetirizine, loratadine, fexofenadine,cetirizine, desloratadine, olopatadine, diphenhydramine, cyproheptadineor hydroxyzine pamoate. In one embodiment, the second therapeutic agentis a H2 receptor antagonist, such as cimetidine, nizatidine, ranitidineor famotidine. In one embodiment, the second therapeutic agent is aleukotriene receptor antagonist or leukotriene synthesis inhibitor, suchas montelukast, zafirlukast, pranlukast, or 5-lipoxygenase inhibitor(e.g., zileuton, hypericum perforatum). In one embodiment, the secondtherapeutic agent is an immunomodulatory agent such as Omalizumab orimmunoglobulin therapy. In one embodiment, the second therapeutic agentis a corticosteroid, such as hydrocortisone, cortisone, ethamethasoneb,triamcinolone, prednisone, prednisolone, or fludrocortisone. In oneembodiment, the second therapeutic agent is a tricylic antidepressantthat can relieve itch such as doxepin, amitriptyline or nortriptyline.In one embodiment, the second therapeutic agent is an anti-inflammatorydrug such as dapsone, sulfasalazine, hydroxycholoroquine or colchicine.In one embodiment, the second therapeutic agent is an immunosuppressantsuch as cyclosporine, methotrexate, mycophenolic acid or tacromilus.

In one embodiment, the second therapeutic agent is an H1 receptorantagonist antihistamine, such as levocetirizine, loratadine,fexofenadine, cetirizine, desloratadine, olopatadine, diphenhydramine,cyproheptadine or hydroxyzine pamoate. In one embodiment, the secondtherapeutic agent is a H2 receptor antagonist, such as cimetidine,nizatidine, ranitidine or famotidine. In one embodiment, the secondtherapeutic agent is a leukotriene receptor antagonist or leukotrienesynthesis inhibitor, such as montelukast, zafirlukast, pranlukast, or5-lipoxygenase inhibitor (e.g., zileuton, hypericum perforatum). In oneembodiment, the second therapeutic agent is an immunomodulatory agentsuch as Omalizumab or immunoglobulin therapy. In one embodiment, thesecond therapeutic agent is a corticosteroid, such as hydrocortisone,cortisone, ethamethasoneb, triamcinolone, prednisone, prednisolone, orfludrocortisone. In one embodiment, the second therapeutic agent is atricylic antidepressant that can relieve itch such as doxepin,amitriptyline or nortriptyline. In one embodiment, the secondtherapeutic agent is an anti-inflammatory drug such as dapsone,sulfasalazine, hydroxycholoroquine or colchicine. In one embodiment, thesecond therapeutic agent is an immunosuppressant such as cyclosporine,methotrexate, mycophenolic acid or tacromilus.

As used herein, the term “pharmaceutically acceptable carrier” refers toany ingredient other than the disclosed compounds, or a pharmaceuticallyacceptable isomer, racemate, hydrate, solvate, isotope or salt thereof(e.g., a carrier capable of suspending or dissolving the activecompound) and having the properties of being nontoxic andnon-inflammatory in a patient. Excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspending or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substances,preserving agents, sweetening agents, or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal, or parenteral, includingintravenous, subcutaneous and/or intramuscular. In one embodiment, theroute of administration is oral. In another embodiment, the route ofadministration is topical.

Dosage forms can be administered once a day, or more than once a day,such as twice or thrice daily. Alternatively, dosage forms can beadministered less frequently than daily, such as every other day, orweekly, if found to be advisable by a prescribing physician or drug'sprescribing information. Dosing regimens include, for example, dosetitration to the extent necessary or useful for the indication to betreated, thus allowing the patient's body to adapt to the treatment, tominimize or avoid unwanted side effects associated with the treatment,and/or to maximize the therapeutic effect of the present compounds.Other dosage forms include delayed or controlled-release forms. Suitabledosage regimens and/or forms include those set out, for example, in thelatest edition of the Physicians' Desk Reference, incorporated herein byreference.

Proper dosages for pediatric patients can be determined using knownmethods, including weight, age, body surface area, and models such asSimcyp® Pediatric Simulation modeling (CERTARA, Princeton, N.J.) whichcan be used to establish a pharmacokinetic approach for dosing thattakes into account patient age, ontogeny of the clearance pathways toeliminate a compound of any one of structures (Ia), (Ia′), (Ib), (Ic) or(Id) or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof, and body surface area (BSA). In one embodiment, thedosage form is formulated to provide a pediatric dose from about 30% toabout 100% of an adult dose, or about 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, or 100% of an adult dose.

In one embodiment, the invention provides an oral pharmaceuticalcomposition comprising a compound of structure (I) or any of thestructures (Ia), (Ia′), (Ib), (Ic) or (Id), or a pharmaceuticallyacceptable salt, isomer, hydrate, solvate or isotope thereof, togetherwith at least one pharmaceutically acceptable oral carrier, diluent, orexcipient. In another embodiment, the invention provides a topicalpharmaceutical composition comprising a compound of structure (I) or anyof the structures (Ia), (Ia′), (Ib), (Ic) or (Id), or a pharmaceuticallyacceptable salt, isomer, hydrate, solvate or isotope thereof, togetherwith at least one pharmaceutically acceptable topical carrier, diluent,or excipient. For example, the oral pharmaceutical composition isprovided to treat cholestatic pruritus, wherein the dosage regimen is,for example, once a day. In one embodiment, the topical pharmaceuticalcomposition is provided to treat atopic dermatitis.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation. In someembodiments, the composition is formulated into a pediatric dosage formsuitable for treating a pediatric subject.

In certain embodiments, the invention provides a compound of structure(I) or any of the structures (Ia), (Ia′), (Ib), (Ic) or (Id), or apharmaceutically acceptable salt, isomer, hydrate, solvate or isotopethereof. Such compounds can be synthesized using standard synthetictechniques known to those skilled in the art. For example, compounds ofthe present invention can be synthesized using appropriately modifiedsynthetic procedures set forth in the following Examples and ReactionSchemes.

To this end, the reactions, processes, and synthetic methods describedherein are not limited to the specific conditions described in thefollowing experimental section, but rather are intended as a guide toone with suitable skill in this field. For example, reactions may becarried out in any suitable solvent, or other reagents to perform thetransformation[s] necessary. Generally, suitable solvents are protic oraprotic solvents which are substantially non-reactive with thereactants, the intermediates or products at the temperatures at whichthe reactions are carried out (i.e., temperatures which may range fromthe freezing to boiling temperatures). A given reaction may be carriedout in one solvent or a mixture of more than one solvent. Depending onthe particular reaction, suitable solvents for a particular work-upfollowing the reaction may be employed.

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art. The compounds and intermediates producedaccording to the methods of the invention may require purification.Purification of organic compounds is well known to a person skilled inthe art and there may be several ways of purifying the same compound. Insome cases, no purification may be necessary. In some cases, thecompounds may be purified by crystallization. In some cases, impuritiesmay be stirred out using a suitable solvent. In some cases, thecompounds may be purified by chromatography, particularly flash columnchromatography, using purpose-made or prepacked silica gel cartridgesand eluents such as gradients of solvents such as heptane, ether, ethylacetate, acetonitrile, ethanol and the like. In some cases, thecompounds may be purified by preparative HPLC using methods asdescribed.

Purification methods as described herein may provide compounds of thepresent invention which possess a sufficiently basic or acidicfunctionality in the form of a salt, such as, in the case of a compoundof the present invention which is sufficiently basic, a trifluoroacetateor formate salt, or, in the case of a compound of the present inventionwhich is sufficiently acidic, an ammonium salt. A salt of this type caneither be transformed into its free base or free acid form,respectively, by various methods known to a person skilled in the art,or be used as salts in subsequent biological assays. It is to beunderstood that the specific form of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

Chemical names were generated using the ChemDraw naming software(Version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases,generally accepted names of commercially available reagents were used inplace of names generated by the naming software.

EXAMPLES General Methods

¹H NMR (400 MHz) spectra were obtained in solution of deuterochloroform(CDCl₃), deuteromethanol (CD₃OD) or dimethyl sulfoxide—D6 (DMSO). HPLCretention times, purities, and mass spectra (LCMS) were obtained usingone of the following methods:

Method 1: Agilent 1260 Infinity II System equipped with an AgilentPoroshell 120 EC-18, 2.7 m, 4.6×100 mm column at 30° C., using H2O with0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acidas the mobile phase B. An ESI detector in positive mode was used. Thegradient was 5-95% mobile phase B over 12 min then held at 95% for 1.8min, then return to 10% mobile phase B over 0.2 min. The flow rate was 1mL/min.

Method 2: SHIMADZU LCMS-2020 equipped with Kinetex® EVO C18 2.1×30 mm 5um column, using H₂O with 0.0375% TFA as mobile phase A, and MeCN with0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase Bfor 0.8 min, held at 95% for 0.15 min, then returned to 5% mobile phaseB for 0.01 min, held at 5% for 0.04 min. The flow rate was 2 mL/min. AnESI detector in positive mode was used.

Method 3: SHIMADZU LCMS-2020 equipped with Kinetex® EVO C18 2.1×30 mm 5um column, using H₂O with 0.0375% TFA as mobile phase A, and MeCN with0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase Bfor 0.6 min, held at 95% for 0.18 min, then returned to 5% mobile phaseB for 0.01 min, held at 5% for 0.01 min. The flow rate was 2 mL/min. AnESI detector in positive mode was used.

Method 4: SHIMADZU LCMS-2020 equipped with Kinetex® EVO C18 2.1×20 mm2.6 um column, using H₂O with 0.0375% TFA as mobile phase A, and MeCNwith 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phaseB for 0.8 min, held at 95% for 0.15 min, then returned to 5% mobilephase B for 0.01 min, held at 5% for 0.04 min. The flow rate was 2mL/min. An ESI detector in positive mode was used.

Method 5: Shimadzu SCL-10A system equipped with Agilent Eclipse XDB-C18,5 uM, 4.6×150 mm column and PE Sciex API 150 EX, using water with 0.1%trifluoroacetic acid as the mobile phase A, and methanol with 0.1%trifluoroacetic acid as the mobile phase B. The gradient was 5-95%mobile phase B over 12 min then held at 95% mobile phase B for 3 min,then return to 5% mobile phase B for 1 min. The flow rate was 1 mL/min.

Method 6: SHIMADZU LCMS-2020 equipped with Kinetex® EVO C18 2.1×30 mmSum column, using H₂O with 0.0375% TFA as mobile phase A, and MeCN with0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase Bfor 0.8 min, held at 95% for 0.29 min, then returned to 5% mobile phaseB for 0.01 min, held at 5% for 0.1 min. The flow rate was 1.5 mL/min. AnESI detector in positive mode was used.

Method 7: SHIMADZU LCMS-2020 equipped with Kinetex® EVO C18 2.1×30 mmSum column, using H₂O with 0.0375% TFA as mobile phase A, and MeCN with0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase Bfor 0.8 min, held at 95% for 0.4 min, then returned to 5% mobile phase Bfor 0.01 min, held at 5% for 0.34 min. The flow rate was 1.5 mL/min. AnESI detector in positive mode was used. Method 8: Agilent 1200\G6110Aequipped with Kinetex® Sum EVO C18 30*2.1 mm column, using H₂O with0.0375% TFA as mobile phase A, and MeCN with 0.01875% TFA as mobilephase B. The gradient was 5-95% mobile phase B for 0.8 min, held at 95%for 0.4 min, then returned to 5% mobile phase B for 0.01 min, held at 5%for 0.29 min. The flow rate was 1.5 mL/min. An ESI detector in positivemode was used.

Method 9: Agilent 1200\G6110A equipped with Chromolith Flash RP-18e25*2.0 mm column, using H₂O with 0.0375% TFA as mobile phase A, and MeCNwith 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phaseB for 0.8 min, held at 95% for 0.4 min, then returned to 5% mobile phaseB for 0.01 min, held at 5% for 0.29 min. The flow rate was 1.5 mL/min.An ESI detector in positive mode was used.

Method 10: Agilent 1200\G1956A equipped with Kinetex EVO C18 30*2.1 mm,5 um column, using H₂O with 0.0375% TFA as mobile phase A, and MeCN with0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phase Bfor 0.8 min, held at 95% for 0.4 min, then returned to 5% mobile phase Bfor 0.01 min, held at 5% for 0.29 min. The flow rate was 1.5 mL/min. AnESI detector in positive mode was used.

Method 11: SHIMADZU LCMS-2020 equipped with Kinetex® EVO C18 2.1×20 mm2.6 um column, using H₂O with 0.0375% TFA as mobile phase A, and MeCNwith 0.01875% TFA as mobile phase B. The gradient was 5-95% mobile phaseB for 0.8 min, held at 95% for 0.15 min, then returned to 5% mobilephase B for 0.01 min, held at 5% for 0.04 min. The flow rate was 2mL/min. An ESI detector in positive mode was used.

Method 12: Agilent 1200 System equipped with a Kinetex C18 50×2.1 mm(Sum particles), using H2O with 0.037% Trifluoroacetic Acid as themobile phase A, and MeCN with 0.018% Trifluoroacetic Acid as the mobilephase B. An ESI detector in positive mode was used. The gradient was 5%B at 0.00 min and 5-90% B at 0.00-0.80 min, 90-95% B at 0.80-0.12 min,and then 95-5% B in 0.01 min, hold on 5% B for 0.34 min, the flow ratewas 1.5 ml/min.

Method 13: Agilent 1260 Infinity II System equipped with an AgilentPoroshell 120 EC-18, 2.7 m, 4.6×100 mm column at 30° C., using H2O with0.1% formic acid as the mobile phase A, and MeCN with 0.1% formic acidas the mobile phase B. An ESI detector in positive mode was used. Thegradient was 5-95% mobile phase B over 5 min then held at 95% for 1.8min, then return to 20% mobile phase B over 0.2 min. The flow rate was 1mL/min.

The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and tolueneused in the procedures were from Aldrich Sure-Seal bottles kept undernitrogen (N₂). Other solvents were used as is. All reactions werestirred magnetically, and temperatures are external reactiontemperatures. Chromatographies were typically carried out using aCombiflash Rf flash purification system (Teledyne Isco) equipped withRedisep (Teledyne Isco) Rf Gold Normal-Phase silica gel (SiO₂) columnsor by using a similar system.

Preparative HPLC purifications were typically performed using one of thefollowing systems: 1) Waters System equipped with a Waters 2489 uv/visdetector, an Aquity QDA detector, a Waters xBridge Prep C18 5 m OBD,30×150 mm column, and eluting with various gradients of H₂O/MeCN (0.1%formic acid) at a 30 mL/min flow rate, 2) Teledyne Isco ACCQPrep® HP150UV system equipped with a Waters xBridge Prep C18 5 m OBD, 30×150 mmcolumn, and eluting with various gradients of H₂O/MeCN (0.1% formicacid) at a 42.5 mL/min flow rate, or 3) column: Phenomenex Synergi C18150×30 mm-4 m; mobile phase: [H₂O (0.225% formic acid)-MeCN]; B %:55%-85%, 12 min) and were typically concentrated using a Genevac EZ-2.

The following additional abbreviations are used: ethyl acetate (EA),triethylamine (TEA), water (H2O, sodium chloride (NaCl), Hydrochloridricacid (HCl), methanol (MeOH), dimethyl sulfoxide (DMSO), silica gel(SiO₂), diisobutylaluminium hydride (DIBAL), trifluoroacetic acid (TFA),4-dimethylaminopyridine (DMAP), diphenylphosphoryl azide (DPPA), benzoylperoxide (BPO), 1,1′-bis(diphenylphosphino)ferrocene (dppf),bis(pinacolato)diboron (B₂pin₂), tetrahydrofuran (THF),1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO),hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU),hydroxybenzotriazole (HOBt), N-methyl morpholine (NMM),N-Bromosuccinimide (NBS), diisopropylethyl amine (DIPEA or DIEA),diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD),2-[2-(dicyclohexylphosphino)phenyl]-N-methylindole (CM-Phos), triflicacid (TfOH), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (EDC), isopropanol (IPA), dimethylformamide (DMF),dimethyl acetamide (DMA), dichloromethane (DCM), 1,2-dichloroethane(DCE), acetonitrile (MeCN or ACN), 1,1′-thiocarbonyldiimidazole (TCDI),petroleum ether (PE), not determined (ND), retention time (RT),molecular weight (mw), room temperature (rt), hour (hr), and notapplicable (N/A).

Example 1

Synthesis of Example 1

Synthesis of tert-butylN-((1S,4S)-[4-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate

To a mixture of tert-butyl cis-N-(4-aminocyclohexyl)carbamate (1.35 g,6.31 mmol, 1 eq.) and TEA (1.28 g, 12.61 mmol, 1.76 mL, 2 eq.) in DCM(20 mL) was added 4-fluorobenzoyl chloride (1 g, 6.31 mmol, 757.58 uL, 1eq.) at 0° C., then the reaction mixture was stirred at 25° C. for 0.5hr. The reaction mixture was concentrated to give a residue that waspurified by silica on column chromatography (eluent: PE/EtOAc=10:1 to1:1). Tert-butyl N-[4-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate (2 g,5.95 mmol, 94.27% yield) was obtained.

Synthesis of cis-N-(4-aminocyclohexyl)-4-fluoro-benzamide·HCl

A mixture of tert-butylN-[4-[(4-fluorobenzoyl)amino]cyclohexyl]carbamate (2 g, 5.95 mmol, 1eq.) in HCl/EtOAc (4 M, 5 mL, 3.36 eq.) was stirred at 25° C. for 1 hr.The reaction mixture was concentrated to give N-(1S,4S)-(4-aminocyclohexyl)-4-fluoro-benzamide·HCl (1.5 g, 5.50 mmol,92.50% yield). It was used as is in the next step directly.

LCMS-ESI (m/z) calculated: 236.3; found 237.4 [M+H]⁺, RT=0.237 min(Method 12)

Synthesis of4-fluoro-N-((1s,4s)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)benzamide

A mixture of 4-bromo-2-(trifluoromethyl)-1-benzothiophene (103 mg, 1 Eq,367 μmol), N-(1S,4S)-(4-aminocyclohexyl)-4-fluoro-benzamide·HCl (100 mg,1 Eq, 367 μmol), cesium carbonate (358 mg, 3 Eq, 1.10 mmol),palladium(II) acetate (4.12 mg, 0.05 Eq, 18.3 μmol), and BINAP (22.8 mg,0.10 Eq, 36.7 μmol) in 1,4-Dioxane (3 mL) was bubbled with nitrogen for5 minutes. The vial was capped and the resulting mixture was stirred at100° C. After stirring for 19 hours, the reaction mixture was cooled toroom temperature. The reaction mixture was filtered, and the filtratewas purified by prep-HPLC to yield4-fluoro-N-((1s,4s)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)benzamide (13.7 mg, 31.4 μmol, 8.56%).

¹H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.22 (d, J=6.6 Hz, 1H), 7.94(dd, J=8.5, 5.6 Hz, 2H), 7.34-7.20 (m, 4H), 6.56 (d, J=7.9 Hz, 1H), 6.09(d, J=5.5 Hz, 1H), 3.97-3.88 (m, 1H), 3.65-3.58 (m, 1H), 1.95-1.83 (m,4H), 1.79-1.63 (m, 4H).

LCMS-ESI (m/z) calculated: 436.47; found 437.2 [M+H]⁺, RT=11.697 min(Method 1)

Example 2 Synthesis of Example 2

Synthesis of Tert-Butyl((1S,3R)-3-(4-methoxybenzamido)cyclohexyl)carbamate

To a stirring solution of an ice-cold solution of(1S,3R)-3-Amino-1-(Boc-amino)cyclohexane (1.142 g, 1.0 eq., 5.329 mmol)in DCM (30 mL) was added with DIPEA (1.377 g, 1.9 mL, 2.0 eq., 10.66mmol), followed by slow addition of 4-methoxybenzoyl chloride (954.5 mg,758 μL, 1.05 eq., 5.595 mmol). The resulting mixture was stirred at roomtemperature. After stirring for 18 hours, the reaction mixture wasfiltered, and the filter cake was washed with DCM and dried under highvacuum to yield tert-butyl((1S,3R)-3-(4-methoxybenzamido)cyclohexyl)carbamate (1.659 g, 4.761mmol, 89.35% yield).

¹H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=7.9 Hz, 1H), 7.82 (d, J=8.4 Hz,2H), 6.97 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.1 Hz, 1H), 3.80 (s, 3H),3.79-3.71 (m, 1H), 3.31-3.22 (m, 1H), 1.93 (d, J=12.0 Hz, 1H), 1.77-1.68(m, 3H), 1.38 (s, 9H), 1.31-1.17 (m, 3H), 1.11-1.01 (m, 1H).

LCMS-ESI (m/z) calculated: 348.44; found 349.2 [M+H]⁺, RT=4.239 min(Method 13).

Synthesis of N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamide·HCl

Methoxybenzamido)cyclohexyl)carbamate (1.654 g, 1 eq., 4.747 mmol) inEtOH (40 mL) was added 1.25M hydrogen chloride in 1,4-dioxane (1.731 g,37.97 mL, 1.25 molar, 10 eq., 47.47 mmol). The resulting mixture wasstirred at 50° C. for 17 hours. The reaction mixture was directlyconcentrated to yield a white solid, which was further dried under highvacuum to yield N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamidehydrochloride (1.331 g, 4.674 mmol, 98.46% yield). It was used withoutfurther purification in the next step.

¹H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=7.9 Hz, 1H), 8.09 (s, 3H), 7.84(d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 3.91-3.81 (m, 1H), 3.80 (s,3H), 3.13-3.05 (m, 1H), 2.12 (d, J=11.6 Hz, 1H), 1.91 (d, J=12.0 Hz,1H), 1.78 (d, J=12.0 Hz, 2H), 1.44-1.21 (m, 4H).

LCMS-ESI (m/z) calculated: 248.44; found 249.2 [M+H]⁺, RT=1.665 min(Method 13).

Synthesis of4-methoxy-N-((1R,3S)-3-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)benzamide

A mixture of 4-bromo-2-(trifluoromethyl)-1-benzothiophene (98.7 mg, 1Eq, 351 μmol), N-((1R,3S)-3-aminocyclohexyl)-4-methoxybenzamidehydrochloride (100 mg, 1 Eq, 351 μmol), cesium carbonate (343 mg, 3 Eq,1.05 mmol), palladium(II) acetate (3.94 mg, 0.05 Eq, 17.6 μmol), andBINAP (21.9 mg, 0.10 Eq, 35.1 μmol) in 1,4-Dioxane (3 mL) was bubbledwith nitrogen for 5 minutes. The vial was capped and the resultingmixture was stirred at 100° C. After stirring for 17.5 hours, thereaction mixture was cooled to room temperature. The reaction mixturewas filtered, and the filtrate was purified by prep-HPLC to yield4-methoxy-N-((1R,3S)-3-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)benzamide (14 mg, 31 μmol, 8.9% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 7.81(d, J=8.4 Hz, 2H), 7.30 (t, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.97(d, J=8.6 Hz, 2H), 6.61 (d, J=7.9 Hz, 1H), 6.20 (d, J=7.9 Hz, 1H),3.99-3.90 (m, 1H), 3.79 (s, 3H), 3.58-3.49 (m, 1H), 2.22 (d, J=12.2 Hz,1H), 2.02 (d, J=12.5 Hz, 1H), 1.84 (t, J=16.5 Hz, 2H), 1.53-1.30 (m,3H), 1.28-1.21 (m, 1H).

LCMS-ESI (m/z) calculated: 448.5; found 449.2 [M+H]⁺, RT=11.163 min(Method 1).

Example 3 Synthesis of Example 3

Synthesis of4-methoxy-N-[(1R,3S)-3-[[2-(trifluoromethyl)benzothiophen-7-yl]amino]cyclohexyl]benzamide

To a solution of 7-bromo-2-(trifluoromethyl)benzothiophene (50 mg,177.88 umol, 1 Eq), N-[(1R,3S)-3-aminocyclohexyl]-4-methoxy-benzamide(53.00 mg, 213.45 umol, 1.2 Eq), RuPhos Pd G4 (14.88 mg, 17.79 umol, 0.1Eq), Cs₂CO₃ (173.87 mg, 533.63 umol, 3 Eq) in dioxane (4 mL) under N2.The reaction mixture was stirred at 100° C. for 12 hr. After return tort, the mixture was filtered. The filtrate was concentrated and purifiedby reversed-phase HPLC to give desired product (23.1 mg, 50.32 umol,20.21% yield).

¹H NMR (400 MHz, DMSO-d6) δ=8.14 (d, J=7.9 Hz, 1H), 8.02 (d, J=1.0 Hz,1H), 7.82 (d, J=8.9 Hz, 2H), 7.35-7.26 (m, 2H), 6.97 (d, J=8.9 Hz, 2H),6.80 (d, J=7.6 Hz, 1H), 5.62 (d, J=8.1 Hz, 1H), 3.98-3.89 (m, 1H), 3.79(s, 3H), 3.62-3.53 (m, 1H), 2.20 (br d, J=11.8 Hz, 1H), 1.99 (br d,J=12.4 Hz, 1H), 1.88-1.77 (m, 2H), 1.52-1.38 (m, 2H), 1.36-1.27 (m, 2H)

LCMS-ESI (m/z) calculated: 448.5; found 449.3 [M+H]⁺, RT=0.718 min(Method 6).

Example 4 Synthesis of Example 4

Synthesis of4-methoxy-N-[(1R,3S)-3-[[2-(trifluoromethyl)-1,3-benzoxazol-4-yl]amino]cyclohexyl]benzamide

To a solution of 4-bromo-2-(trifluoromethyl)-1,3-benzoxazole (70 mg,263.14 umol, 1 Eq), N-[(1R,3S)-3-aminocyclohexyl]-4-methoxy-benzamide(78.41 mg, 315.77 umol, 1.2 Eq), Pd2(dba)3 (48.19 mg, 52.63 umol, 0.2Eq) Xantphos (30.45 mg, 52.63 umol, 0.2 Eq) and Cs₂CO₃ (257.21 mg,789.43 umol, 3 Eq) in toluene (5 mL) under N2. The reaction mixture wasstirred at 100° C. for 12 hr. After return to rt, the mixture wasfiltered through a pad of celite. The filtrate was concentrated undervacuum and the residue was purified by reversed-phase HPLC to yield4-methoxy-N-[(1R,3S)-3-[[2-(trifluoromethyl)-1,3-benzoxazol-4-yl]amino]cyclohexyl]benzamide(2.8 mg, 6.24 umol, 2.37% yield).

¹H NMR (400 MHz, DMSO-d6) δ=8.15 (d, J=7.8 Hz, 1H), 7.84-7.80 (m, 2H),7.35 (t, J=8.3 Hz, 1H), 6.98-6.93 (m, 3H), 6.68 (d, J=8.3 Hz, 1H), 6.32(br d, J=8.8 Hz, 1H), 3.97-3.88 (m, 1H), 3.79 (s, 3H), 3.68 (td, J=3.4,7.4 Hz, 1H), 2.14 (br d, J=10.6 Hz, 1H), 1.94 (br d, J=11.9 Hz, 1H),1.86-1.77 (m, 2H), 1.47-1.37 (m, 2H), 1.34-1.26 (m, 2H)

LCMS-ESI (m/z) calculated: 433.42; found 434.3 [M+H]⁺, RT=0.699 min(Method 9).

The compounds listed in Table 1 were made using the procedures of Scheme1.

TABLE 1 Purity Ob- Cpd RT served Purity Reaction Structure No. (min) MWm/z Ion Method Conditions

1-1 0.883 432.44 433.4 [M + H]⁺ method 7 DavePhos- PdG3, t- BuONa,dioxane

1-2 0.729 449.49 450.3 [M + H]⁺ method 6 RuPhosPdG4, Cs2CO3, dioxane

1-3 0.568 438.59 439.1 [M + H]⁺ method 8 RuPhosPdG4, Cs2CO3, dioxane

1-4 0.641 422.54 423 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-5 0.734 410.51 411.2 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-6 0.645 426.55 427.3 [M + H]⁺ Method 6 Xantphos, Pd2(OAc)3, Cs2CO3,Toluene

1-7 0.619 445.486 446.4 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-8 0.664 430.51 431.3 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-9 0.589 408.56 409 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-10 0.542 394.53 395.4 [M + H]⁺ Method 9 Xantphos, Pd2(OAc)3, C2sCO3,Toluene

1-11 0.595 382.5 393.3 [M + H]⁺ Method 9 Xantphos, Pd2(OAc)3, C2sCO3,Toluene

1-12 0.703 396.52 397.1 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-13 0.703 418.48 419 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-14 0.529 410.53 411.3 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-15 0.564 398.5 399.3 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-16 0.680 405.52 406.1 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-17 0.736 449.49 450.4 [M + H]⁺ Method 8 RuPhosPdG4, Cs2CO3, dioxane

1-18 0.745 436.47 437.2 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-19 0.783 437.46 438.1 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-20 0.700 393.48 394.0 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-21 0.642 432.447 433.2 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-22 0.69  449.49 450.4 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-23 0.601 446.474 447.2 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-24 0.708 466.89 467 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-25 0.441 432.447 433.2 [M + H]⁺ Method 2 RuPhosPdG3, Cs2CO3, dioxane

1-26 0.499 446.474 447.2 [M + H]⁺ Method 4 RuPhosPdG3, Cs2CO3, dioxane

1-27 0.553 466.89 467.2 [M + H]⁺ Method 4 RuPhosPdG3, Cs2CO3, dioxane

1-28 0.528 446.474 447.2 [M + H]⁺ Method 4 RuPhosPdG3, Cs2CO3, dioxane

1-29 0.503 466.89 467.1 [M + H]⁺ Method 2 RuPhosPdG3, Cs2CO3, dioxane

1-30 0.554 450.438 451.1 [M + H]⁺ Method 4 RuPhosPdG3, Cs2CO3, dioxane

1-31 0.553 450.438 451 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-32 0.555 450.438 451 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-33 0.601 450.438 451 [M + H]⁺ Method 2 RuPhosPdG3, Cs2CO3, dioxane

1-34 0.541 450.438 451.1 [M + H]⁺ Method 2 RuPhosPdG3, Cs2CO3, dioxane

1-35 0.669 433.431 434.4 [M + H]⁺ Method 6 Xantphos, Pd2(OAc)3, Cs2CO3,t- amyl alcohol

1-36 0.539 450.438 451.1 [M + H]⁺ Method 4 XantPhos- PdG3, Cs2CO3,dioxane

1-37 0.56  466.89 467.1 [M + H]⁺ Method 6 XantPhos- PdG3, Cs2CO3,dioxane

1-38 0.646 466.89 467.4 [M + H]⁺ Method 6 XantPhos- Pd,G3, Cs2CO3, t-amyl alcohol

1-39 0.621 466.89 467.4 [M + H]⁺ Method 6 RuPhosPdG3, Cs2CO3, dioxane

1-40 0.557 446.474 447.2 [M + H]⁺ Method 11 RuPhosPdG3, Cs2CO3, dioxane

1-41 0.425 414.457 415.3 [M + H]⁺ Method 9 RuPhosPdG4, Cs2CO3, dioxane

1-42 0.489 440.547 441.4 [M + H]⁺ Method 9 RuPhosPdG4, Cs2CO3, dioxane

1-43 0.536 389.459 390.3 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

1-44 0.654 432.447 433.4 [M + H]⁺ Method 6 RuPhosPdG4, Cs2CO3, dioxane

Example 5 Synthesis of Example 5

Synthesis of Tert-Butyl((1S,4S)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)Carbamate

To a sealed tube containing 4-bromo-2-(trifluoromethyl)benzo[b]thiophene(500 mg, 1.1 Eq, 18 mmol) in toluene (50 mL) was added tert-butyl((1S,4S)-4-aminocyclohexyl)carbamate (350 mg, 1 Eq, 16.3 mmol), andsodium tert-butoxide (173 mg, 1 Eq., 18 mmol) in THE (5 mL) followed byPd(dppf)₂Cl₂-DCM (147 mg, 0.1 Eq, 1.8 mmol). The tube was purged with N₂three times and then sealed. The reaction mixture was heated to 110° C.for 3 hr. Solvent was removed under vacuo and the resulting cruderesidue was acidified with TFA and purified by reversed-phase C18 column(10-100% MeOH/H₂O with 0.1% TFA) to yield a mixture of tert-butyl((1S,4S)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)carbamate(45 mg, 7% yield) and(1S,4S)-N1-(2-(trifluoromethyl)benzo[b]thiophen-4-yl)cyclohexane-1,4-diamineas TFA salt (26 mg, 4% yield).

LCMS-ESI (m/z) calculated: 414.49; found 415.5 [M+H]⁺, RT=5.54 min(Method 5).

Synthesis of(1S,4S)-N1-(2-(trifluoromethyl)benzo[b]thiophen-4-yl)cyclohexane-1,4-diamine

To a solution of tert-butyl((1S,4S)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)carbamate (45 mg, 1 Eq, 0.011 mmol) in DCM (2 mL) was addedTFA (2 mL). The reaction mixture was stirred for 2 hr and concentratedunder vacuo to provide the title compound(1S,4S)-N1-(2-(trifluoromethyl)benzo[b]thiophen-4-yl)cyclohexane-1,4-diamine.

LCMS-ESI (m/z) calculated: 314.1; found 315.2 [M+H]⁺, RT=4.23 min(Method 5).

Synthesis of3-cyano-N-((1S,4S)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)benzamide

To 3-cyanobenzoic acid (3.0 mg, 1.1 Eq, 0.020 mmol) in DMF (2 mL), wasadded HATU (6.5 mg, 1.05 Eq, 0.018 mmol), followed by(1S,4S)-N1-(2-(trifluoromethyl)benzo[b]thiophen-4-yl)cyclohexane-1,4-diamineTFA salt (8 mg, 1 Eq, 0.019 mmol). DIEA (9.9 mg, 4 Eq, 0.077 mmol) wasadded and the reaction mixture was stirred at rt for 16 hr. The reactionmixture was acidified with TFA and purified by RP-C18 ISCO (10-100%MeOH/H₂O, 0.1% TFA) to yield1-methyl-N-((1S,4S)-4-((2-(trifluoromethyl)benzo[b]thiophen-4-yl)amino)cyclohexyl)-1,2,3,4-tetrahydroquinoline-6-carboxamideas TFA salt (5 mg, 48% yield).

LCMS-ESI (m/z) calculated: 443.1; found 444.5 [M+H]⁺, RT=13.37 min(Method 5).

Example 6 Synthesis of Example 6

Synthesis of 3-amino-1-(2, 2-difluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5 yl]amino]cyclohexyl]pyrazole-4-carboxamide

To a solution of 3-amino-N-[4-[[2-(trifluoromethyl) imidazo [1, 2-a]pyridin-5-yl]amino] cyclohexyl]-1H-pyrazole-4-carboxamide (50 mg, 122.73umol, N/A purity, 1 eq) and Cs₂CO₃ (79.98 mg, 245.46 umol, 2 eq) in MeCN(3 mL) was added 2, 2-difluoroethyl trifluoromethanesulfonate (52.56 mg,245.46 umol, 2 eq), the reaction solution was stirred at 60° C. for 1 h.The reaction solution was filtered by filter membrane. The crude productwas purified by Prep-HPLC with the following conditions: column:Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B%: 27%-57%, 10 min. and lyophilized to give 3-amino-1-(2,2-difluoroethyl)-N-[4-[[2-(trifluoromethyl) imidazo[1,2-a]pyridin-5yl]amino]cyclohexyl]pyrazole-4-carboxamide (6.3 mg, 12.78 umol, 10.41%yield, 95.6% purity).

LCMS-ESI (m/z) calculated: 471.4; found 472.2 [M+H]⁺, RT=0.408 min(Method 4).

¹H NMR) (400 MHz, DMSO-d₆) δ=8.71 (s, 1H), 8.11 (s, 1H), 7.60 (d, J=6.6Hz, 1H), 7.42-7.24 (m, 1H), 6.95 (d, J=8.9 Hz, 1H), 6.46 (d, J=4.8 Hz,1H), 6.42 (t, J=3.5 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 5.82-5.16 (m, 2H),4.37 (dt, J=3.6, 15.1 Hz, 2H), 3.92-3.80 (m, 1H), 3.67 (s, 1H),1.96-1.86 (m, 2H), 1.86-1.72 (m, 4H), 1.70-1.61 (m, 2H).

Example 7 Synthesis of Example 7

Synthesis of3-amino-1-(2,2,2-trifluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]]cyclohexyl]pyrazole-4-carboxamide

To a solution of 3-amino-N-[4-[[2-(trifluoromethyl) imidazo [1, 2-a]pyridin-5-yl]amino] cyclohexyl]-1H-pyrazole-4-carboxamide (50 mg, 122.73umol, N/A purity, 1 eq) and Cs2CO3 (79.98 mg, 245.46 umol, 2 eq) in MeCN(3 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (28.49mg, 122.73 umol, 1 eq), the reaction solution was stirred at 50° C. for1 h. The reaction solution was filtered by filter membrane. The crudeproduct was purified by Prep-HPLC with the following conditions: column:Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water(FA)-ACN]; B %:31%-61%, 10 min. and lyophilized to give3-amino-1-(2,2,2-trifluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide(15.5 mg, 25.73% yield) was obtained.

LCMS-ESI (m/z) calculated: 489.4; found 490.0 [M+H] ⁺, RT=0.471 min(Method 2).

1H NMR (400 MHz, DMSO-d₆) δ=8.72 (s, 1H), 8.17 (s, 1H), 7.69 (d, J=6.6Hz, 1H), 7.35 (dd, J=7.8, 8.7 Hz, 1H), 6.95 (d, J=8.9 Hz, 1H), 6.46 (d,J=4.8 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 5.65-5.44 (m, 2H), 4.89 (q, J=9.1Hz, 2H), 3.93-3.77 (m, 1H), 3.68 (s, 1H), 1.96-1.86 (m, 2H), 1.86-1.72(m, 4H), 1.70-1.61 (m, 2H).

Example 8 Synthesis of Example 8

Synthesis of Ethyl1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

To a solution of ethyl 1H-pyrazole-4-carboxylate (10 g, 71.36 mmol, 1eq) in THE (150 mL) was added NaH (3.42 g, 85.63 mmol, 60% purity, 1.2eq) at 0° C. and stirred for 1h under N₂. Then added2-(chloromethoxy)ethyl-trimethyl-silane (14.28 g, 85.63 mmol, 15.16 mL,1.2 eq) and stirred for 2 h at 25° C. The reaction was quenched withsaturated NH₄Cl aqueous (200 mL) and extracted with EtOAc (100 mL*3).The combined organic layers were washed with brine, dried over Na₂SO₄,concentrated. The residue was purified by column chromatography (SiO2,Petroleum ether/Ethyl acetate=I/O to 80/20). (TLC, PE:EtOAc=5:1,Rf=0.5). ethyl 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate(19 g, 70.27 mmol, 98.47% yield, N/A purity) was obtained as a lightyellow oil.

LCMS-ESI (m/z) calculated: 270.1; found 271.2 [M+H]⁺, RT=0.511 min(Method 4).

¹H NMR (400 MHz, DMSO-d₆) δ=8.49 (s, 1H), 7.91 (s, 1H), 5.44 (s, 2H),4.22 (q, J=7.1 Hz, 2H), 3.57-3.52 (m, 2H), 1.26 (t, J=7.1 Hz, 3H),0.85-0.80 (m, 2H), −0.06 (s, 9H).

Synthesis of Ethyl5-formyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

To a solution of ethyl1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (19 g, 70.27mmol, 1 eq) in THE (200 mL) was added dropwise of LDA (2 M, 52.70 mL,1.5 eq) at −70° C. over 10 min. After stirred for 30 min, DMF (30.82 g,421.60 mmol, 32.44 mL, 6 eq) was added. The resulting mixture wasstirred at −70° C. for another 20 min. The reaction mixture was slowlypoured into saturated NH₄Cl aqueous (200 mL) and keep the temperature at0-10° C., extracted with EtOAc (100 mL*3). The combined organic layerswere washed with brine, dried over Na₂SO₄, concentrated. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=I/O to 74/26). (TLC, PE:EtOAc=5:1, Rf=0.65). ethyl5-formyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (5.8 g,19.44 mmol, 27.66% yield) was obtained as light yellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ=10.34 (s, 1H), 8.09 (s, 1H), 5.72 (s, 2H),4.32 (q, J=7.1 Hz, 2H), 3.58-3.53 (m, 2H), 1.31 (t, J=7.1 Hz, 3H),0.83-0.79 (m, 2H), −0.08 (s, 9H)

Synthesis of Ethyl5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

To a solution of ethyl5-formyl-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (2 g,6.70 mmol, 1 eq) in DCM (15 mL) was added DAST (1.62 g, 10.05 mmol, 1.33mL, 1.5 eq) at 0° C. and stirred for 2 h at 25° C. The reaction mixtureconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO2, Petroleum ether/Ethylacetate=1/0 to 0/1). (TLC, PE:EtOAc=5:1, Rf=0.8). ethyl5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate(1.6 g, 4.99 mmol, 74.51% yield, N/A purity) was obtained as colorlessoil.

LCMS-ESI (m/z) calculated: 320.1; found 321.1 [M+H]⁺, RT=0.516 min(Method 4).

¹H NMR (400 MHz, DMSO-d₆) δ=8.04 (s, 1H), 7.54 (t, J=52.2 Hz, 1H), 5.62(s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.61-3.55 (m, 2H), 1.29 (t, J=7.1 Hz,3H), 0.86-0.81 (m, 2H), −0.07 (s, 9H).

Synthesis of5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylicAcid

To a solution of ethyl5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate(200 mg, 624.21 umol, 1 eq) in THE (1.5 mL), H₂O (1.5 mL) was addedLiOH·H₂O (78.58 mg, 1.87 mmol, 3 eq) and stirred for 2 h at 25° C. Thenadded LiOH·H₂O (78.58 mg, 1.87 mmol, 3 eq) and stirred for 12 h at 25°C. The reaction mixture was neutralized 5% HCl to PH 7. The reactionmixture concentrated under reduced pressure to give a residue. Theresidue was directly used for next step without purification.5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylicacid (180 mg, 615.69 umol, 98.64% yield, N/A purity) was obtained aswhite solid.

LCMS-ESI (m/z) calculated: 292.1; found 293.2 [M+H]⁺, RT=0.532 min(Method 2).

¹H NMR (400 MHz, DMSO-d₆) δ=8.04 (s, 1H), 7.54 (t, J=52.2 Hz, 1H), 5.62(s, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.61-3.55 (m, 2H), 1.29 (t, J=7.1 Hz,3H), 0.86-0.81 (m, 2H), −0.07 (s, 9H).

Synthesis of5-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxamide

To a solution of5-(difluoromethyl)-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylicacid (160 mg, 547.28 umol, 1 eq),N4-[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]cyclohexane-1,4-diamine(183.21 mg, 547.28 umol, 1 eq, HCl) in DMF (4 mL) was added HATU (312.14mg, 820.92 umol, 1.5 eq) DIEA (212.20 mg, 1.64 mmol, 285.98 uL, 3 eq)and stirred for 1.5 h at 25° C. The mixture was partitioned betweenEtOAc (10 mL) and water (10 mL). The aqueous phase was extracted withEtOAc (10 mL*2). Organic phase were dried over MgSO4, and concentratedunder vacuum. The residue was purified by column chromatography (SiO2,Petroleum ether/Ethyl acetate=I/O to 20/1). (TLC, PE:EtOAc=1:1, Rf=0.5).5-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxamide(210 mg, 366.72 umol, 67.01% yield, N/A purity) was obtained as whitesolid.

LCMS-ESI (m/z) calculated: 572.2; found 573.5 [M+H]⁺, RT=0.612 min(Method 2).

¹H NMR (400 MHz, DMSO-d₆) δ=8.77 (s, 1H), 8.33-8.22 (m, 2H), 7.76 (t,J=52.9 Hz, 1H), 7.46-7.35 (m, 1H), 7.02 (d, J=8.9 Hz, 1H), 6.51 (d,J=4.6 Hz, 1H), 6.17 (d, J=7.6 Hz, 1H), 5.62 (s, 2H), 4.01-3.91 (m, 1H),3.76 (s, 1H), 3.64 (t, J=8.1 Hz, 2H), 2.03-1.79 (m, 6H), 1.78-1.69 (m,2H), 0.95-0.84 (m, 2H), 0.00 (s, 9H).

Synthesis of3-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-Carboxamide

To a solution of5-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxamide(200 mg, 349.26 umol, 1 eq) in DCM (2 mL) was added TFA (616.00 mg, 5.40mmol, 400.00 uL, 15.47 eq) and stirred for 1 h at 25° C. The reactionmixture concentrated under reduced pressure to give a residue. Thenadded K₂CO₃ (241.35 mg, 1.75 mmol, 5 eq), MeOH (2 mL) and stirred for 1h at 50° C. The mixture was partitioned between EtOAc (10 mL) and water(10 mL). The aqueous phase was extracted with EtOAc (10 mL*2). Organicphase were dried over MgSO4, and concentrated under vacuum. The residuewas directly used for next step without purification.3-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-carboxamide(150 mg, 301.77 umol, 86.40% yield, 89% purity) was obtained.

LCMS-ESI (m/z) calculated: 442.1; found 443.3 [M+H]⁺, RT=0.424 min(Method 2).

¹H NMR (400 MHz, DMSO-d₆) δ=13.54 (d, J=2.0 Hz, 1H), 8.75 (s, 1H),8.60-8.36 (m, 1H), 7.91 (d, J=6.0 Hz, 1H), 7.57-7.24 (m, 2H), 6.99 (d,J=8.9 Hz, 1H), 6.53-6.42 (m, 1H), 6.15 (d, J=7.6 Hz, 1H), 3.93 (dd,J=3.7, 6.4 Hz, 1H), 3.73 (s, 1H), 2.00-1.69 (m, 8H).

Synthesis of1-(2,2-difluoroethyl)-3-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide

Example 8

To a solution of3-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-carboxamide(75 mg, 150.89 umol, 89% purity, 1 eq) 2,2-difluoroethyltrifluoromethanesulfonate (32.31 mg, 150.89 umol, 1 eq) in MeCN (2 mL)was added Cs₂CO₃ (98.32 mg, 301.77 umol, 2 eq) and stirred for 12 h at50° C. The mixture was filtered to remove the insoluble. The crudeproduct was purified by reversed-phase HPLC:Column (Phenomenex luna C18150*25 mm*10 um) Condition water((0.225% FA)-ACN) Begin B (41) End B(71) Gradient Time(min) (10). and lyophilized to give desired product1-(2,2-difluoroethyl)-3-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide(6.2 mg, 12.13 umol, 8.04% yield, 99.1% purity).

LCMS-ESI (m/z) calculated: 506.1; found 507.1 [M+H]⁺, RT=0.461 min(Method 4).

¹H NMR (400 MHz, DMSO-d₆) δ=8.72 (s, 1H), 8.49 (s, 1H), 8.09 (d, J=6.8Hz, 1H), 7.53-7.21 (m, 2H), 6.96 (d, J=8.9 Hz, 1H), 6.63-6.25 (m, 2H),6.11 (d, J=7.6 Hz, 1H), 4.77 (dt, J=2.8, 15.6 Hz, 2H), 3.89 (d, J=3.0Hz, 1H), 3.69 (s, 1H), 1.96-1.74 (m, 6H), 1.72-1.63 (m, 2H).

Example 9 Synthesis of Example 9

Synthesis of3-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide

Example 9

To a solution of3-(difluoromethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-carboxamide(75 mg, 150.89 umol, 89% purity, 1 eq) 2,2,2-trifluoroethyltrifluoromethanesulfonate (35.02 mg, 150.89 umol, 1 eq) in MeCN (2 mL)was added Cs₂CO₃ (98.32 mg, 301.77 umol, 2 eq) and stirred for 12 h at50° C. The mixture was filtered to removed the insoluble. The crudeproduct was purified by reversed-phase HPLC:Column (Phenomenex luna C18150*25 mm*10 um) Condition water((0.225% FA)-ACN) Begin B (39) End B(69) Gradient Time(min) (9) and lyophilized to give3-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide (8.5 mg, 16.06 umol, 10.65% yield, 99.1% purity).

LCMS-ESI (m/z) calculated: 524.1; found 525.2 [M+H]⁺, RT=0.482 min(Method 2).

¹H NMR (400 MHz, DMSO-d₆) δ=8.72 (s, 1H), 8.55 (s, 1H), 8.24-8.11 (m,1H), 7.54-7.21 (m, 2H), 6.96 (d, J=8.9 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H),6.11 (d, J=7.8 Hz, 1H), 5.34 (q, J=9.1 Hz, 2H), 3.96-3.79 (m, 1H), 3.70(s, 1H), 1.97-1.73 (m, 6H), 1.72-1.60 (m, 2H).

Example 10 Synthesis of Example 10

Synthesis of3-chloro-1-(2-fluoroethyl)-N-((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide

To a solution of3-chloro-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-carboxamide(50 mg, 117.14 umol, 1 eq), 1-fluoro-2-iodo-ethane (20.38 mg, 117.14umol, 1 eq) in MeCN (2 mL) was added Cs₂CO₃ (114.50 mg, 351.43 umol, 3eq). The reaction was stirred at 50° C. for 2 hr. The reaction mixturewas filtered through the filter membrane. The filtrate was purified byPrep-HPLC with the following conditions column: Phenomenex luna C18150*25 mm*10 um; mobile phase: [water(FA)-ACN]; B %: 32%-62%, 10.5 min.The compound3-chloro-1-(2-fluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide(5.3 mg, 11.12 umol, 9.49% yield, 99.2% purity) was obtained as whitesolid.

LCMS-ESI (m/z) calculated: 472.1; found 472.9 [M+H]⁺, RT=0.520 min(Method 2).

¹H NMR (400 MHz, DMSO-d6) δ=8.71 (s, 1H). 8.36 (s, 1H) 7.70 (d, J=6.63Hz, 1H) 7.35 (t, J=8.25 Hz, 1H) 6.95 (d, J=8.88 Hz, 1H) 6.48 (d, J=5.13Hz, 1H) 6.11 (d, J=7.63 Hz, 1H) 4.65-4.89 (m, 2H) 4.35-4.52 (m, 2H) 3.91(s, 1H) 3.66 (s, 1H) 1.74-1.91 (m, 6H) 1.69 (dd, J=8.94, 3.81 Hz, 2H).

Example 11 Synthesis of Example 11

Synthesis of3-chloro-1-(2,2-difluoroethyl)-N-((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide

To a solution of3-chloro-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-carboxamide(50 mg, 117.14 umol, 1 eq), 1,1-difluoro-2-iodo-ethane (22.49 mg, 117.14umol, 1 eq) in MeCN (2 mL) was added Cs₂CO₃ (114.50 mg, 351.43 umol, 3eq). The reaction was stirred at 50° C. for 14 hr. The reaction mixturewas filtered through the filter membrane. The filtrate was purified byPrep-HPLC with the following conditions column: Phenomenex luna C18150*25 mm*10 um; mobile phase: [water(FA)-ACN]; B %: 34%-64%, 10.5 min.The compound3-chloro-1-(2,2-difluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide(3.9 mg, 7.81 umol, 6.67% yield, 98.3% purity) was obtained as yellowsolid.

LCMS-ESI (m/z) calculated: 490.1; found 491.2 [M+H]⁺, RT=0.539 min(Method 2).

¹HNMR (400 MHz, DMSO-d₆) δ=8.71 (s, 1H) 8.36 (s, 1H) 7.79 (d, J=6.63 Hz,1H) 7.35 (t, J=8.25 Hz, 1H) 6.95 (d, J=8.88 Hz, 1H) 6.45-6.59 (m, 1H)6.22-6.43 (m, 1H) 6.11 (d, J=7.63 Hz, 1H) 4.65 (td, J=15.26, 3.13 Hz,2H) 3.90 (s, 1H) 3.66 (s, 1H) 1.74-1.96 (m, 6H) 1.69 (dd, J=8.94, 3.81Hz, 2H).

Example 12 Synthesis of Example 12

Synthesis of3-chloro-1-(2,2,2-trifluoroethyl)-N-((1s,4s)-4-((2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)amino)cyclohexyl)-1H-pyrazole-4-carboxamide

To a solution of3-chloro-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]-1H-pyrazole-4-carboxamide(50 mg, 117.14 umol, 1 eq), 2,2,2-trifluoroethyltrifluoromethanesulfonate (27.19 mg, 117.14 umol, 1 eq) in MeCN (2 mL)was added Cs₂CO₃ (114.50 mg, 351.43 umol, 3 eq). The reaction wasstirred at 50° C. for 2 hr. The reaction mixture was filtered throughthe filter membrane. The filtrate was purified by Prep-HPLC with thefollowing conditions column: Phenomenex luna C18 150*25 mm*10 um; mobilephase: [water(FA)-ACN]; B %: 37%-67%, 10.5 min. The compound3-chloro-1-(2,2,2-trifluoroethyl)-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl]amino]cyclohexyl]pyrazole-4-carboxamide(16.3 mg, 32.03 umol, 27.34% yield, 100% purity) was obtained.

LCMS-ESI (m/z) calculated: 508.1; found 508.9 [M+H]⁺, RT=0.560 mi(Method 2).

¹HNMR (400 MHz, DMSO-d₆) δ=8.71 (s, 1H) 8.40 (s, 1H) 7.88 (d, J=6.63 Hz,1H) 7.35 (t, J=8.25 Hz, 1H) 6.95 (d, J=8.88 Hz, 1H) 6.46 (d, J=4.88 Hz,1H) 6.11 (d, J=7.63 Hz, 1H) 5.21 (q, J=9.05 Hz, 2H) 3.90 (d, J=2.63 Hz,1H) 3.67 (s, 1H) 1.75-1.95 (m, 6H) 1.61-1.74 (m, 2(H).

The compounds listed in Table 2 were made using the procedures of Scheme2.

TABLE 2 Purity Cpd RT Observed Purity Structure No. (min) MW m/z IonMethod

2-1 13.86 458.1 459.2 [M + H]⁺ Method 5

2-2 13.18 475.1 476.1 [M + H]⁺ Method 5

2-3 13.28 436.1 437.2 [M + H]⁺ Method 5

2-4 14.54 487.2 488.5 [M + H]⁺ Method 5

2-5 13.4 471.2 472.2 [M + H]⁺ Method 5

2-6 13.14 511.1 512.4 [M + H]⁺ Method 5

2-7 12.73 458.1 459.4 [M + H]⁺ Method 5

2-8 0.619 487.527 488 [M + H]⁺ Method 6

2-9 0.637 442.446 443 [M + H]⁺ Method 6

2-10 0.614 442.446 443 [M + H]⁺ Method 6

2-11 0.437 392.386 393 [M + H]⁺ Method 6

2-12 0.573 431.423 432 [M + H]⁺ Method 6

2-13 0.548 442.446 443 [M + H]⁺ Method 6

2-14 0.679 495.498 496 [M + H]⁺ Method 6

2-15 0.634 447.462 448 [M + H]⁺ Method 6

2-16 0.662 461.489 462 [M + H]⁺ Method 6

2-17 0.462 432.451 433 [M + H]⁺ Method 6

2-18 0.465 442.446 443 [M + H]⁺ Method 6

2-19 0.597 407.397 408 [M + H]⁺ Method 6

2-20 0.671 462.521 463 [M + H]⁺ Method 6

2-21 0.588 434.467 435 [M + H]⁺ Method 6

2-22 0.646 499.461 500 [M + H]⁺ Method 6

2-23 0.656 499.461 500 [M + H]⁺ Method 2

2-24 0.332 424.456 425.1 [M + H]⁺ Method 2

2-25 0.421 442.442 443.1 [M + H]⁺ Method 2

2-26 0.344 422.86 423 [M + H]⁺ Method 2

2-27 0.439 432.447 433.1 [M + H]⁺ Method 2

2-28 0.538 511.497 512.1 [M + H]⁺ Method 2

2-29 0.553 456.473 457.1 [M + H]⁺ Method 2

2-30 .563 406.413 407 [M + H]⁺ Method 7

2-31 .631 459.49 459.9 [M + H]⁺ Method 7

2-32 0.424 458.85 459 [M + H]⁺ Method 2

2-33 0.304 463.481 464.2 [M + H]⁺ Method 3

2-34 0.3 445.49 446.2 [M + H]⁺ Method 3

2-35 0.456 529.94 530.2 [M + H]⁺ Method 3

2-36 0.531 407.401 408.1 [M + H]⁺ Method 6

2-37 0.539 443.434 444.1 [M + H]⁺ Method 6

2-38 0.452 442.446 443.1 [M + H]⁺ Method 6

2-39 0.567 456.421 457.2 [M + H]⁺ Method 6

2-40 0.574 456.473 457.2 [M + H]⁺ Method 6

2-41 0.524 443.434 444.2 [M + H]⁺ Method 6

2-42 0.668 450.89 451.1 [M + H]⁺ Method 6

2-43 0.598 434.467 435.2 [M + H]⁺ Method 6

2-44 0.605 478.476 479.2 [M + H]⁺ Method 6

2-45 0.632 478.476 479.2 [M + H]⁺ Method 6

2-46 0.582 474.411 475.2 [M + H]⁺ Method 6

2-47 0.523 417.396 418.1 [M + H]⁺ Method 6

2-48 0.558 434.467 435.2 [M + H]⁺ Method 6

2-49 0.683 499.461 500.2 [M + H]⁺ Method 6

2-50 0.58 443.43 444.2 [M + H]⁺ Method 6

2-51 0.533 422.412 423.2 [M + H]⁺ Method 6

2-52 0.626 459.49 460.2 [M + H]⁺ Method 6

2-53 0.364 427.5 428.2 [M + H]⁺ Method 4

2-54 0.392 455.53 456.2 [M + H]⁺ Method 4

2-55 0.334 402.45 403.2 [M + H]⁺ Method 4

2-56 0.353 478.496 479.2 [M + H]⁺ Method 4

2-57 0.37 401.462 402.2 [M + H]⁺ Method 4

2-58 0.432 397.87 398.1 [M + H]⁺ Method 4

2-59 0.382 442.446 443.1 [M + H]⁺ Method 4

2-60 0.406 481.471 482.2 [M + H]⁺ Method 4

2-61 0.385 463.481 464.2 [M + H]⁺ Method 4

2-62 0.322 439.471 440.2 [M + H]⁺ Method 4

2-63 0.334 413.433 414.1 [M + H]⁺ Method 4

2-64 0.282 424.456 425.1 [M + H]⁺ Method 4

2-65 0.38 424.456 425.2 [M + H]⁺ Method 4

2-66 0.467 445.49 446.4 [M + H]⁺ Method 6

2-67 0.549 523.58 524.4 [M + H]⁺ Method 6

2-68 0.557 436.86 437.3 [M + H]⁺ Method 6

2-69 0.522 427.431 428.3 [M + H]⁺ Method 6

2-70 0.579 432.447 433.4 [M + H]⁺ Method 6

2-71 0.553 431.463 432.4 [M + H]⁺ Method 6

2-72 0.606 436.86 437.3 [M + H]⁺ Method 6

2-73 0.532 403.409 404.3 [M + H]⁺ Method 6

2-74 0.407 403.409 404.3 [M + H]⁺ Method 6

2-75 0.533 433.435 434.4 [M + H]⁺ Method 6

2-76 0.429 419.412 420.3 [M + H]⁺ Method 6

2-77 0.449 393.374 394.3 [M + H]⁺ Method 6

2-78 0.555 427.431 428.4 [M + H]⁺ Method 6

2-79 0.451 431.463 432.4 [M + H]⁺ Method 6

2-80 0.503 495.52 496.3 [M + H]⁺ Method 6

2-81 0.602 436.86 437.3 [M + H]⁺ Method 6

2-82 0.549 427.431 428.3 [M + H]⁺ Method 6

2-83 0.506 431.463 432.4 [M + H]⁺ Method 6

2-84 0.501 495.52 496.4 [M + H]⁺ Method 6

2-85 0.432 404.397 405.3 [M + H]⁺ Method 6

2-86 0.526 514.95 515.3 [M + H]⁺ Method 6

2-87 0.476 432.451 433.4 [M + H]⁺ Method 6

2-88 0.566 455.485 456.3 [M + H]⁺ Method 6

2-89 0.498 459.473 460.4 [M + H]⁺ Method 6

2-90 0.581 416.448 417.4 [M + H]⁺ Method 6

2-91 0.615 430.475 431.4 [M + H]⁺ Method 6

2-92 0.466 460.461 461.4 [M + H]⁺ Method 6

2-93 0.584 416.448 417.3 [M + H]⁺ Method 6

2-94 0.615 430.475 431.4 [M + H]⁺ Method 6

2-95 0.566 460.457 461.4 [M + H]⁺ Method 6

2-96 0.494 459.473 460.4 [M + H]⁺ Method 6

2-97 0.583 430.475 431.4 [M + H]⁺ Method 6

2-98 0.500 442.446 443.3 [M + H]⁺ Method 6

2-99 0.561 456.473 457.3 [M + H]⁺ Method 6

2-100 0.558 471.488 472.4 [M + H]⁺ Method 6

2-101 0.382 406.413 407.3 [M + H]⁺ Method 6

2-102 0.46 406.413 407.3 [M + H]⁺ Method 6

2-103 0.466 469.472 470.4 [M + H]⁺ Method 6

2-104 0.404 442.446 443.3 [M + H]⁺ Method 6

2-105 0.401 456.473 457.4 [M + H]⁺ Method 6

2-106 0.527 460.437 461.4 [M + H]⁺ Method 6

2-107 0.556 477.88 478.3 [M + H]⁺ Method 6

2-108 0.541 446.478 447.4 [M + H]⁺ Method 6

2-109 0.533 460.437 461.4 [M + H]⁺ Method 6

2-110 0.519 471.44 472.4 [M + H]⁺ Method 6

2-111 0.573 459.449 460.4 [M + H]⁺ Method 6

2-112 0.474 420.44 421.4 [M + H]⁺ Method 6

2-113 0.483 420.44 421.4 [M + H]⁺ Method 6

2-114 0.437 392.386 393.4 [M + H]⁺ Method 6

2-115 0.488 406.413 407.4 [M + H]⁺ Method 6

2-116 0.525 420.44 421.4 [M + H]⁺ Method 6

2-117 0.425 419.408 420.4 [M + H]⁺ Method 6

2-118 0.441 445.49 446.4 [M + H]⁺ Method 6

2-119 0.571 456.473 457.4 [M + H]⁺ Method 6

2-120 0.548 460.437 461.4 [M + H]⁺ Method 6

2-121 0.647 472.53 473.4 [M + H]⁺ Method 6

2-122 0.644 456.469 457.4 [M + H]⁺ Method 6

2-123 0.548 442.446 443.4 [M + H]⁺ Method 6

2-124 0.473 443.434 444.4 [M + H]⁺ Method 6

2-125 0.384 443.434 444.4 [M + H]⁺ Method 6

2-126 0.470 443.434 444.3 [M + H]⁺ Method 6

2-127 0.47 420.44 421.4 [M + H]⁺ Method 6

2-128 0.455 392.386 393.4 [M + H]⁺ Method 6

2-129 0.552 434.467 435.5 [M + H]⁺ Method 6

2-130 0.382 417.436 418.4 [M + H]⁺ Method 6

2-131 0.398 417.436 418.4 [M + H]⁺ Method 6

2-132 0.524 436.439 437.4 [M + H]⁺ Method 6

2-133 0.442 421.428 422.4 [M + H]⁺ Method 6

2-134 0.373 420.44 421.4 [M + H]⁺ Method 6

2-135 0.489 456.421 457.5 [M + H]⁺ Method 6

2-136 0.552 456.421 457.5 [M + H]⁺ Method 6

2-137 0.515 440.86 441.5 [M + H]⁺ Method 6

2-138 0.45 406.413 407.4 [M + H]⁺ Method 6

2-139 0.498 423.46 424.4 [M + H]⁺ Method 6

2-140 0.576 448.494 449.4 [M + H]⁺ Method 6

2-141 0.468 432.451 433.4 [M + H]⁺ Method 6

2-142 0.443 463.481 464.2 [M + H]⁺ Method 2

2-143 0.46 481.471 482.2 [M + H]⁺ Method 2

2-144 0.362 438.483 439.2 [M + H]⁺ Method 2

2-145 0.342 387.435 388.2 [M + H]⁺ Method 2

2-146 0.33 388.423 389.2 [M + H]⁺ Method 2

2-147 0.329 391.44 392.1 [M + H]⁺ Method 2

2-148 0.397 448.9 449.2 [M + H]⁺ Method 2

2-149 0.383 436.86 437.1 [M + H]⁺ Method 2

2-150 0.334 464.469 465.2 [M + H]⁺ Method 2

2-151 0.427 474.464 475.2 [M + H]⁺ Method 2

2-152 0.584 422.496 423.2 [M + H]⁺ Method 2

2-153 0.527 460.437 461.2 [M + H]⁺ Method 2

2-154 .454 424.45 425.3 [M + H]⁺ Method 9

2-155 .529 509.55 510.4 [M + H]⁺ Method 9

2-156 .558 432.447 433.4 [M + H]⁺ Method 9

2-157 .567 420.412 421.3 [M + H]⁺ Method 9

2-158 .547 445.49 446.4 [M + H]⁺ Method 9

2-159 .612 463.481 464.4 [M + H]⁺ Method 9

2-160 0.548 455.485 456.3 [M + H]⁺ Method 2

2-161 0.426 435.479 436.1 [M + H]⁺ Method 2

2-162 0.391 403.409 404.2 [M + H]⁺ Method 6

2-163 0.39 442.446 443.2 [M + H]⁺ Method 6

2-164 0.509 457.461 458.3 [M + H]⁺ Method 6

2-165 0.509 442.446 443.2 [M + H]⁺ Method 6

2-166 0.608 472.468 473.3 [M + H]⁺ Method 6

2-167 0.613 460.433 461.2 [M + H]⁺ Method 6

2-168 0.468 442.446 443.3 [M + H]⁺ Method 6

2-169 0.582 473.52 474.2 [M + H]⁺ Method 6

2-170 0.607 459.49 460.2 [M + H]⁺ Method 6

2-171 0.466 443.434 444.2 [M + H]⁺ Method 6

2-172 0.655 487.91 488.3 [M + H]⁺ Method 6

2-173 0.645 490.91 491.2 [M + H]⁺ Method 6

2-174 0.444 443.434 444.2 [M + H]⁺ Method 6

2-175 0.5 436.439 437.1 [M + H]⁺ Method 6

2-176 0.483 426.83 427 [M + H]⁺ Method 6

2-177 0.503 460.384 461.1 [M + H]⁺ Method 6

2-178 0.577 481.471 482.2 [M + H]⁺ Method 6

2-179 0.582 452.429 453.1 [M + H]⁺ Method 6

2-180 0.569 481.471 482.2 [M + H]⁺ Method 6

2-181 0.595 495.498 496.2 [M + H]⁺ Method 6

2-182 0.466 456.473 457.2 [M + H]⁺ Method 6

2-183 0.562 456.473 457.1 [M + H]⁺ Method 6

2-184 0.416 460.505 461.2 [M + H]⁺ Method 6

2-185 0.480 434.423 435.1 [M + H]⁺ Method 6

2-186 0.464 420.44 421.1 [M + H]⁺ Method 6

2-187 0.531 474.411 475.1 [M + H]⁺ Method 6

2-188 0.604 481.471 482.2 [M + H]⁺ Method 6

2-189 0.398 446.478 447.1 [M + H]⁺ Method 6

2-190 0.561 448.494 449.2 [M + H]⁺ Method 6

2-191 0.499 446.478 447.3 [M + H]⁺ Method 2

2-192 0.576 486.87 487.1 [M + H]⁺ Method 2

2-193 0.39 424.456 425.3 [M + H]⁺ Method 2

2-194 0.36 453.446 454.1 [M + H]⁺ Method 2

2-195 0.409 413.473 414.3 [M + H]⁺ Method 2

2-196 0.424 432.447 433.3 [M + H]⁺ Method 2

2-197 0.397 466.485 467.2 [M + H]⁺ Method 2

2-198 0.542 469.512 470.3 [M + H]⁺ Method 2

2-199 0.404 470.5 471.2 [M + H]⁺ Method 2

2-200 0.456 470.5 471.2 [M + H]⁺ Method 2

2-201 0.622 441.458 442.3 [M + H]⁺ Method 10

2-202 0.515 470.46 471.4 [M + H]⁺ Method 10

2-203 0.613 523.58 524.2 [M + H]⁺ Method 6

2-204 0.537 481.49 482.2 [M + H]⁺ Method 6

2-205 0.505 480.51 481.3 [M + H]⁺ Method 6

2-206 0.476 500.57 501.4 [M + H]⁺ Method 6

2-207 0.715 494.94 495.2 [M + H]⁺ Method 6

2-208 0.45 442.446 443.1 [M + H]⁺ Method 6

2-209 0.501 443.434 444.2 [M + H]⁺ Method 6

2-210 0.496 443.434 444.2 [M + H]⁺ Method 6

2-211 0.439 431.463 432.2 [M + H]⁺ Method 6

2-212 0.407 407.401 408.2 [M + H]⁺ Method 2

2-213 0.504 456.421 457.2 [M + H]⁺ Method 2

2-214 0.409 496.486 497.3 [M + H]⁺ Method 2

2-215 0.4 398.458 399.2 [M + H]⁺ Method 2

2-216 0.29 399.446 400.2 [M + H]⁺ Method 2

2-217 0.287 400.434 401.2 [M + H]⁺ Method 2

2-218 0.386 446.474 447.3 [M + H]⁺ Method 2

2-219 0.342 443.449 444.3 [M + H]⁺ Method 2

2-220 0.393 474.411 475.2 [M + H]⁺ Method 2

2-221 0.398 437.443 438.3 [M + H]⁺ Method 2

2-222 0.421 445.49 446.3 [M + H]⁺ Method 2

2-223 0.38 445.49 446.4 [M + H]⁺ Method 2

2-224 0.417 464.469 465.3 [M + H]⁺ Method 2

2-225 0.422 444.483 445.2 [M + H]⁺ Method 2

2-226 0.383 444.483 445.3 [M + H]⁺ Method 2

2-227 0.573 469.512 470.3 [M + H]⁺ Method 2

2-228 0.592 492.402 493.2 [M + H]⁺ Method 2

2-229 0.545 467.404 468.3 [M + H]⁺ Method 2

2-230 0.518 464.465 465.3 [M + H]⁺ Method 2

2-231 .45 442.446 443.4 [M + H]⁺ Method 8

2-232 .603 441.458 422.4 [M + H]⁺ Method 8

2-233 0.539 407.401 408.1 [M + H]⁺ Method 6

2-234 0.472 456.473 457.1 [M + H]⁺ Method 6

2-235 0.586 443.434 444.1 [M + H]⁺ Method 6

2-236 0.58 407.397 408.1 [M + H]⁺ Method 6

2-237 0.642 474.411 475.1 [M + H]⁺ Method 6

2-238 0.62 405.425 406.1 [M + H]⁺ Method 6

2-239 0.597 474.411 475.1 [M + H]⁺ Method 6

2-240 0.618 468.484 469.2 [M + H]⁺ Method 6

2-241 0.459 443.434 444.1 [M + H]⁺ Method 6

2-242 0.52 402.421 403.2 [M + H]⁺ Method 11

2-243 0.456 456.473 457.2 [M + H]⁺ Method 11

2-244 0.479 393.37 394.2 [M + H]⁺ Method 11

2-245 0.497 446.478 447.2 [M + H]⁺ Method 11

2-246 0.444 421.428 422.3 [M + H]⁺ Method 11

2-247 0.446 457.461 458 [M + H]⁺ Method 2

2-248 0.408 414.457 415.1 [M + H]⁺ Method 2

2-249 0.408 438.483 439.2 [M + H]⁺ Method 2

2-250 0.32 413.473 414.1 [M + H]⁺ Method 2

2-251 0.375 415.445 416.1 [M + H]⁺ Method 2

2-252 0.399 384.431 385.1 [M + H]⁺ Method 2

2-253 0.356 425.444 426.1 [M + H]⁺ Method 2

2-254 0.355 403.409 404 [M + H]⁺ Method 2

2-255 0.376 416.477 417.1 [M + H]⁺ Method 2

2-256 0.368 416.477 417.1 [M + H]⁺ Method 2

2-257 0.424 482.94 483.1 [M + H]⁺ Method 2

2-258 0.474 402.502 403.1 [M + H]⁺ Method 2

2-259 0.441 388.475 389.1 [M + H]⁺ Method 2

2-260 0.493 389.459 390.1 [M + H]⁺ Method 2

2-261 0.487 377.423 378 [M + H]⁺ Method 2

2-262 0.469 388.475 389.2 [M + H]⁺ Method 2

2-263 0.51 373.46 374.2 [M + H]⁺ Method 2

2-264 0.528 393.88 394.1 [M + H]⁺ Method 2

2-265 0.522 393.88 394 [M + H]⁺ Method 2

2-266 0.503 373.46 374 [M + H]⁺ Method 2

2-267 0.486 413.485 414.3 [M + H]⁺ Method 2

2-268 0.417 377.452 378.2 [M + H]⁺ Method 2

2-269 0.356 503.506 504.2 [M + H]⁺ Method 3

2-270 0.315 467.473 468.2 [M + H]⁺ Method 3

2-271 0.447 547.93 548 [M + H]⁺ Method 3

2-272 0.364 456.473 457.3 [M + H]⁺ Method 3

2-273 0.424 398.458 398.9 [M + H]⁺ Method 2

2-274 0.448 477.508 478.2 [M + H]⁺ Method 2

2-275 0.449 453.31 453 [M + H]⁺ Method 2

2-276 0.395 413.473 414 [M + H]⁺ Method 2

2-277 0.443 418.87 418.9 [M + H]⁺ Method 2

2-278 0.44 418.87 419 [M + H]⁺ Method 2

2-279 0.389 456.421 457 [M + H]⁺ Method 2

2-280 0.416 402.421 403.1 [M + H]⁺ Method 2

2-281 0.565 417.444 418 [M + H]⁺ Method 2

2-282 0.518 474.411 474.9 [M + H]⁺ Method 2

2-283 0.392 480.94 481.1 [M + H]⁺ Method 2

2-284 0.555 506.429 506.9 [M + H]⁺ Method 2

2-285 0.439 434.439 434.9 [M + H]⁺ Method 2

2-286 0.388 438.431 438.9 [M + H]⁺ Method 2

2-287 0.385 416.477 416.9 [M + H]⁺ Method 2

2-288 0.416 467.473 468 [M + H]+ Method 2

2-289 8.225 455.485 456 [M + H]+ Method 1

2-290 9.400 443.43 443.9 [M + H]+ Method 1

2-291 8.375 489.93 489.9 [M + H]+ Method 1

2-292 7.458 454.88 454.9 [M + H]+ Method 1

2-293 7.675 454.88 454.9 [M + H]+ Method 1

2-294 8.303 468.91 469 [M + H]+ Method 1

2-295 0.347 476.84 477.1 [M + H]+ Method 3

2-296 0.557 446.474 447.2 [M + H]+ Method 11

2-297 0.523 476.84 477.2 [M + H]+ Method 2

Example 13 Synthesis of Example 13

Synthesis of 2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-ol

A solution of 2-aminopyrimidin-4-ol (2 g, 18.00 mmol, 1 eq) and3-bromo-1,1,1-trifluoro-propan-2-one (3.44 g, 18.00 mmol, 1.87 mL, 1 eq)in EtOH (15 mL). The reaction was stirred at 130° C. for 2 hr undermicrowave. The reaction mixture was dissolved in MeOH and filtered by afilter membrane. The filtrate was purified by reversed phase HPLC (0.1%FA in water, MeCN) to give a crude product. The crude product waspurified by column chromatography on silica gel eluting with (SiO₂,Petroleum ether/Ethyl acetate=I/O to 3/2, Rf=0.60, The TLC (petroleumether/ethyl acetate=0/1) indicated new spots (Rf=0.70, Rf=0.60, Rf=0.40)formed.). The filtrate was purified by reversed phase HPLC (0.1% FA inwater, MeCN) to give a pure product. Compound2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-ol (200 mg, 984.63 umol,5.47% yield, N/A purity) was obtained as white solid.

LCMS-ESI (m/z) calculated: 203.1; found 204.1 [M+H]⁺, RT=0.411 min(Method 11).

¹H NMR (400 MHz, DMSO-d₆) δ=13.26-12.88 (m, 1H), 8.17 (d, J=1.3 Hz, 1H),8.01 (d, J=7.5 Hz, 1H), 5.82 (d, J=7.5 Hz, 1H).

Synthesis of 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine

To a solution of 2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-ol (50 mg,246.16 umol, 1 eq) in POCl₃ (1 mL) at 25° C., the reaction solution washeated to 100° C., the mixture was stirred at 100° C. for 2 hr. Thereaction mixture was concentrated under reduced pressure to removePOCl₃. The residue was purified by prep-TLC (SiO₂, Petroleum ether:Ethylacetate=1:1) collect point of Rf=0.6. Compound5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine (41 mg, 181.34umol, 73.67% yield, 98% purity) was obtained as a white solid.

LCMS-ESI (m/z) calculated: 221.5; found 222.0 [M+H]⁺, RT=0.339 min(Method 11).

Synthesis of4-methoxy-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-yl]amino]cyclohexyl]benzamide

A mixture of 5-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine (41mg, 185.05 umol, 1 eq), N-(4-aminocyclohexyl)-4-methoxy-benzamide (91.90mg, 370.09 umol, 2 eq) and TEA (56.17 mg, 555.14 umol, 77.27 uL, 3 eq)in NMP (2 mL), the mixture was stirred at 25° C. for 12 hr under N₂atmosphere. The reaction solution was filtered by a filter membrane. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi Polar-RP100*25 mm*4 um; mobile phase:[water(0.225% FA)-ACN]; B %: 26%-56%, 8min). Compound4-methoxy-N-[4-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-5-yl]amino]cyclohexyl]benzamide(23.9 mg, 53.43 umol, 28.88% yield, 96.9% purity) was obtained.

LCMS-ESI (m/z) calculated: 433.4; found 434.2 [M+H]⁺, RT=0.446 min(Method 4).

¹H NMR (400 MHz, DMSO-d₆) δ=8.73 (d, J=0.9 Hz, 1H), 8.31 (d, J=5.4 Hz,1H), 7.99 (d, J=6.0 Hz, 1H), 7.91-7.80 (m, 2H), 7.55 (d, J=6.3 Hz, 1H),6.99 (d, J=8.9 Hz, 2H), 6.33 (d, J=5.6 Hz, 1H), 3.97-3.89 (m, 1H), 3.81(s, 4H), 1.98-1.87 (m, 4H), 1.85-1.76 (m, 2H), 1.74-1.63 (m, 2H).

Example 14 Mrgprx2 Activity

CHO cells stably transfected to express human MRGPRX2 were maintained inan incubator at 37° C. with 5% CO2 and grown in F12 (HAM) media with 10%fetal bovine serum (FBS), 1% Glutamax, 1% penicillin/streptomycin, 800pg/mL Geneticin (G418), and 300 pg/mL Hygromycin B. Cells were plated ina 384-well assay plate at 20,000 cells per well in 12 μL of Opti-MEM andkept in an incubator overnight. On the day of the assay, compoundssolubilized at 10 mM in DMSO were added as a 10-point curve (30 uM finaltop concentration with 1:3 serial dilutions) using a Tecan D300E digitaldispenser. Agonists were diluted in assay buffer (final concentrationsof 5.7 mM Tris-HCl, 43 mM NaCl, 50 mM LiCl, pH=8) and 2 μL of theagonist Cortistatin-14 (CPC Scientific, catalog CORT-002) are added toeach well. Final concentrations of agonists were 0.3 μM Cortistatin-14.Final concentrations of DMSO were kept consistent across the plate.Plates were incubated in the dark for 1 hr at 37° C. and then for 1 hrat room temperature. IP-1 standards and HTRF detection reagents wereadded according to the IP-One-Gq Kit purchased from Cisbio (part number62IPAPEJ) and incubated in the dark for 1 hr at room temperature. Theplate was read on a Molecular Devices SpectraMax iD5 plate reader. TheHTRF ratio was calculated from the raw data and graphed using GraphPadPrism to calculate an IC50 value for each compound.

Activity data for selected MRGPRX2 antagonists (versus 0.3 uMCorstitatin-14 agonist) are displayed in Table 3. The activity rangesare denoted as follows: “+++++” denotes antagonist activity<50 nM;“++++” denotes antagonist activity between 51 and 100 nM; “+++” denotesactivity between 101 and 500 nM; “++” denotes activity between 501 and1000 nM; and “+” denotes activity>1000 nM

TABLE 3 MRGPR2 Antagonist Cpd No. Activity Example 1 +++ Example 4 ++Example 5 +++ example 6 +++++ Example 7 +++++ Example 8 +++++ Example 9+++++ Example 11 +++++ Example 12 +++++ Example 2 +++ 1-1 +++++ 1-3 +1-4 + 1-5 +++ 1-13 ++++ 1-14 + 1-16 +++ 1-17 + 1-19 ++++ 1-20 ++++ 1-21++++ 1-22 ++++ 1-23 +++ 1-30 ++++ 1-31 ++++ 2-1 ++++ 2-2 + 2-3 +++ 2-5+++ 2-6 ++++ 2-8 +++++ 2-9 +++ 2-10 +++++ 2-11 +++ 2-14 ++++ 2-15 +++2-23 +++++ 2-24 +++++ 2-27 +++ 2-28 +++++ 2-120 +++++ 2-125 +++ 2-126+++++ 2-134 +++ 2-135 +++++ 2-137 +++++ 2-138 +++++ 2-141 +++++ 2-142+++++ 2-143 +++++ 2-147 +++ 2-148 ++++ 2-149 +++ 2-150 +++++ 2-151 +++2-153 +++++ 2-157 +++++ 2-158 +++++ 2-159 ++++ 2-160 +++++ 2-162 +++2-163 +++++ 2-165 +++++ 2-166 ++++ 2-168 +++++ 2-169 +++++ 2-176 +++++2-177 +++++ 2-178 +++++ 2-179 +++++ 2-180 +++++ 2-181 +++++ 2-183 +++++2-188 +++++ 2-190 +++ 2-191 ++++ 2-193 +++++ 2-194 +++++ 2-195 +++++2-198 +++++ 2-201 +++++ 2-202 +++++ 2-203 +++++ 2-204 +++++ 2-207 +++2-208 ++++ 2-218 +++++ 2-220 +++++ 2-221 +++++ 2-227 +++ 2-228 +++++2-229 +++++ 2-230 +++++ 2-231 +++++ 2-232 +++++ 2-233 +++ 2-241 +++2-245 +++ 2-246 +++++ 2-247 +++ 2-253 +++++ 2-254 +++ 2-255 +++ 2-257+++++ 2-258 +++++ 2-259 +++ 2-260 +++ 2-262 +++ 2-269 +++ 2-270 ++++2-274 +++++ 2-275 +++ 2-276 ++++ 2-283 +++ 2-284 +++ 2-285 ++++ 2-286+++ 2-288 +++++ 2-289 +++++ 2-290 +++ 2-291 +++++ 2-292 +++ 2-293 +++++2-294 +++++ 2-295 ++++ 2-297 +++++

Example 15 Mast Cell Beta-Hexosaminidase Release Assay

Human LAD2 cells (NIH) were maintained in an incubator at 37° C. with 5%CO₂ and cultured in StemPro-34 serum-free media (Gibco 10639011)supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 50 mg/mlstreptomycin and 100 ng/ml SCF (Invitrogen PEP0860), at a concentrationof 2-5×10⁵ cells/mL, with hemidepletion every 1-2 weeks.

Cells were transferred to SCF-Free medium at 2.5×10⁵ cells/mL and keptin an incubator overnight. On the day of the assay, cells were washedtwice in Assay Buffer (final concentrations 10 mM HEPES, 137 mM NaCl,5.6 mM D-glucose, 2.7 mM KCl, 1 mM MgCl, 1.8 mM CalCl₂, 0.4 mMNa₂HPO₄·7H₂O, 0.04% BSA, pH=7.4) and plated in a 96-well v-bottom plateat 20,000 cells per well in 80 μL Assay Buffer. Antagonist compoundssolubilized at 10 mM in DMSO were diluted in Assay Buffer to 10× finaldesired concentrations as a 10-point curve (10 μM final topconcentration with 1:3 serial dilutions) and 10 μL added per well.Plates were then incubated for 1 hour at 37° C. Agonists were diluted inAssay Buffer to 10× desired concentrations and 10 μL of the appropriateagonist added to each well. The final concentration of Cortistatin-14(Tocris 3374) used in antagonist assays was 500 nM. Final concentrationsof DMSO were kept consistent across the plate. Plates were thenincubated in a warm air oven for 30 minutes at 37° C., followed bycentrifugation at 4° C. for 5 minutes at 450×g. 50 μL supernatant fromeach well was then transferred to a 96-well flat bottom plate containing100 μL substrate solution per well (3.5 mg/mLp-Nitrophenyl-N-acetyl-β-D-glucosaminide (Sigma 487052) in CitrateBuffer containing a final concentration of 40 mM Citric Acid, 20 mMNa₂HPO₄·7H₂O, pH=4.5). To the cell pellets left in the remaining assaybuffer, 150 μL 0.1% Triton-X-100 was then added to each well,resuspended by pipetting up and down, and 50 μL cell lysates transferredto a second 96-well flat bottom plate containing 100 μL substratesolution per well. Plates containing transferred supernatant and celllysates were then incubated in a warm air oven for 90 minutes at 37° C.After incubation, 50 μL of 400 mM Glycine buffer (pH 10.7) was addedinto each well and the plate was read on a Molecular Devices SpectraMaxiD5 plate reader (absorbance at 405 nm with reference filter at 620 nm).After background subtraction, the percentage degranulation (percentbeta-hexosaminidase release) was calculated as 100×(supernatantvalues)/(supernatant+lysate values), followed by analysis using GraphPadPrism software to calculate an IC₅₀ value for each compound.

Activity data for selected MRGPRX2 antagonists in the Mast CellBeta-Hexosaminidase Release Assay are displayed in Table 4. The activityranges are denoted as follows: “+++++” denotes antagonist activity<50nM; “++++” denotes antagonist activity between 51 and 100 nM; “+++”denotes activity between 101 and 500 nM; “++” denotes activity between501 and 1000 nM; and “+” denotes activity>1000 nM.

TABLE 4 MRGPRX2 Antagonist Cpd No. Activity Example 1 +++++ 1-1 +++++2-6 +++++ 2-10 +++++ 2-24 +++++ 2-28 +++++ 2-52 +++++ 2-61 +++++ 2-71+++++ 2-137 +++++ 2-142 +++++ 2-143 +++++ 2-153 +++++ 2-160 +++++ 2-178+++++ 2-222 +++++ 2-228 +++++

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary, to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

This application claims the benefit of priority to U.S. ProvisionalApplication No. 63/130,525, filed Dec. 24, 2020, which application ishereby incorporated by reference in its entirety.

1. A method of treating a MRGPRX2 or a MRGPRX2 ortholog dependentcondition by administering to a subject in need thereof an effectiveamount of a compound having structure (I):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof, wherein: R¹ is cycloalkyl, aryl, heterocyclyl,—(CH₂)_(n)Q, —CHQR, or —CQ(R)₂, wherein R¹ is optionally substitutedwith one or more R^(q1); Q is C₁₋₆ alkyl, aryl, cycloalkyl,heterocyclyl, —CH₂C(O)OR, —C(O)OR, —C(O)NHR, haloalkyl, —CN, —N(R)₂,—N(R)C(O)R, —N(R)C(O)OR, or —N(R)S(O)₂R, wherein Q is optionallysubstituted with one or more R^(q2); R^(q1) and R^(q2) are independentlyH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocyclyl, —OR, —O(CH₂)_(n)R, haloalkoxy, —C(O)OR, —C(O)R, —OC(O)R,halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, S(O)₂R, —C(H)Q′R,or —(CH₂)_(n)Q′ where Q′ is selected from C₁₋₆ alkyl, aryl, cycloalkyl,heterocyclyl, OR′, —C(O)OR′, —OC(O)R′, haloalkyl, —CN, —N(R′)₂,—N(R′)C(O)R′, and —N(R′)S(O)₂R′; A is N or CR^(a); B is N or CR^(b); Cis N or CR^(c); D is CR^(d); E is N or CR^(e); G is N or CR^(g); W isCR^(w); Y is N, S or CR^(y); Z is N, CR^(z), S or O; each R isindependently H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, alkylamino,—(CH₂)_(n)R′, halo, aryl, cycloalkyl, heteroaryl or heterocyclyl, or twoR groups taken together with the atom to which they are attached form acarbocyle or heterocycle; R′ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl; R^(a)is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN,—N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R; R^(b) is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR,—C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R,or S(O)₂R; R^(c) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo,haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R; R^(d) iseither absent, or when present, H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR,—OC(O)R, halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, orS(O)₂R; R^(e) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR,—C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R,or S(O)₂R; R^(g) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR,—C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R,or S(O)₂R; R^(w) is either absent, or when present, H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR,—C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R,or S(O)₂R; R^(y) is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo,haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R; R^(z) is H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂,—N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R; n is independently 0, 1, 2, 3, 4 and5; R⁶ is C₁₋₄ alkyl, phenyl, —C(O)R, —(CH₂)_(n)OR, —CN, F, Cl, Br, CF₃,CF₂H or CFH₂, with the proviso that R is not H; each R⁸ is independentlyH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, haloalkyl, —CN, —N(R)₂,—N(R)C(O)R, —N(R)S(O)₂R, or S(O)₂R; R², R³, R⁴, R⁵ and R⁷ are the sameor different and either absent or, when present, independently H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocyclyl, —OR, —C(O)OR, —OC(O)R, halo, —CN, —N(R)₂, —N(R)C(O)R,—N(R)S(O)₂R, or S(O)₂R; wherein: adjacent atoms on either the “a” ringor “b” ring may be joined together by single bonds to form a 9 atomcarbocyclic or heterocyclic ring structure; or atoms 1 and 2, 3 and 4, 5and 6 and 8 and 9 on rings “a” ring and “b” ring may be joined togetherby double bonds to form an aromatic 9 atom carbocyclic or heterocyclicring structure; or atoms 1 and 2, 3 and 4, 6 and 7 and 8 and 9 on rings“a” ring and “b” ring may be joined together by double bonds to form anaromatic 9 atom carbocyclic or heterocyclic ring structure; with theprovisos that: when Z is S or N, then A and C cannot both be N; and whenZ is N, then C and G cannot both be N.
 2. The method of claim 1, whereinthe compound has one of the following structures (Ia) or (Ia′):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof.
 3. The method of claim 1, wherein the compound has oneof the following structures (Ib), (Ic) or (Id):

or a pharmaceutically acceptable salt, isomer, hydrate, solvate orisotope thereof.
 4. The method of 1, wherein R¹ is aryl, —(CH₂)_(n)Q,—CHQR, or —CQ(R)₂, wherein R¹ is optionally substituted with one or moreR^(q1); Q is aryl, —CH₂C(O)OR, —C(O)OR, —C(O)NHR, haloalkyl, —CN,—N(R)₂, —N(R)C(O)R, —N(R)C(O)OR, or —N(R)S(O)₂R, wherein Q is optionallysubstituted with one or more R^(q2).
 5. The method of claim 4, whereinR¹ is phenyl.
 6. The method of claim 5, wherein phenyl is unsubstituted.7. The method of claim 5, wherein phenyl is substituted with one or moreR^(q1).
 8. The method of claim 7, wherein R^(q1) is H, —OR, —N(R)S(O)₂R,—CN, —N(R)C(O)R or —C(H)Q′R.
 9. The method of claim 1, wherein R¹ isheterocyclyl, —(CH₂)_(n)Q, —CHQR, or —CQ(R)₂, wherein R¹ is optionallysubstituted with one or more R^(q1); Q is heterocyclyl, —CH₂C(O)OR,—C(O)OR, —C(O)NHR, haloalkyl, —CN, —N(R)₂, —N(R)C(O)R, —N(R)C(O)OR, or—N(R)S(O)₂R, wherein Q is optionally substituted with one or moreR^(q2).
 10. The method claim 9, wherein the heterocyclyl isunsubstituted.
 11. The method of claim 10, wherein the heterocyclyl issubstituted with one or more R^(q1).
 12. The method of claim 11, whereinR^(q1) is H or C₁₋₆ alkyl.
 13. The method of claim 1, wherein R⁶ is CF₃,CF₂H, CFH₂, C₁₋₆ alkyl, —C(O)R, —(CH₂)_(n)OR or —CN.
 14. The method ofclaim 13, wherein R⁶ is CF₃.
 15. The method of claim 13, wherein R⁶ isCF₂H.
 16. The method of claim 13, wherein R⁶ is C₁₋₆ alkyl.
 17. Themethod of claim 13, wherein R⁶ is —C(O)R.
 18. The method of claim 17,wherein R is C₁₋₆ alkyl.
 19. The method of claim 13, wherein R⁶ is—(CH₂)_(n)OR.
 20. The method of claim 19, wherein n is
 0. 21. The methodof claim 19, wherein n is
 1. 22. The method of claim 21, wherein R isC₁₋₆ alkyl.
 23. The method of claim 13, wherein R⁶ is —CN.
 24. Themethod of claim 1, wherein each R⁸ is H.
 25. The method of claim 1,wherein Z is N or S.
 26. The method of claim 1, wherein each of A, B, C,and Y are CH.
 27. The method of claim 1, wherein E is N.
 28. The methodof claim 1, wherein R^(w) is absent.
 29. The method of claim 1, whereinatoms 1 and 2, 3 and 4, 5 and 6 and 8 and 9 on rings “a” ring and “b”ring are joined together by double bonds to form an aromatic 9 atomheterocyclic ring structure.
 30. The method of claim 1, wherein atoms 1and 2, 3 and 4, 6 and 7 and 8 and 9 on rings “a” ring and “b” ring arejoined together by double bonds to form an aromatic 9 atom heterocyclicring structure.
 31. The method of claim 1 wherein the compound isselected from any one of the following compounds, or a pharmaceuticallyacceptable salt, isomer, hydrate, solvate or isotope thereof:

32-34. (canceled)
 35. The method of claim 1, wherein the MRGPRX2 orMRGPRX2 ortholog dependent condition is a pseudo-allergic reaction, anitch associated condition, a pain associated condition, or aninflammatory or autoimmune disorder.
 36. The method of claim 35, whereinthe itch associated condition is chronic itch; contact dermatitis;Allergic blepharitis; Anemia; Atopic dermatitis; Bullous pemphigoid;Candidiasis; Chicken pox; end-stage renal failure; hemodialysis; Chronicurticaria; Contact dermatitis, Atopic Dermatitis; Dermatitisherpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis;Ectopic eczema; Eosinophilic fasciitis; Epidermolysis bullosa;Erythrasma; Food allergy; Folliculitis; Fungal skin infection;Hemorrhoids; Herpes; HIV infection; Hodgkin's disease; Hyperthyroidism;Iodinated contrast dye allergy; Iron deficiency anemia; Kidney disease;Leukemia, porphyrias; Lymphoma; Malignancy; Mastocystosis; Multiplemyeloma; Neurodermatitis; Onchocerciasis; Paget's disease; Pediculosis;Polycythemia rubra vera; Prurigo nodularis; Lichen Planus; LichenSclerosis; Pruritus ani; Pseudorabies; Psoriasis; Rectal prolapse;Sarcoidosis granulomas; Scabies; Schistosomiasis; Scleroderma, Severestress, Stasia dermatitis; Swimmer's itch; Thyroid disease; Tineacruris; Rosacea; Cutaneous amyloidosis; Scleroderma; Acne; woundhealing; burn healing; ocular itch; or Urticaria.
 37. The method ofclaim 36, wherein the itch associated condition is urticaria, pruritus,atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.38. The method of claim 35, wherein the pain associated condition isAcute Pain, Advanced Prostate Cancer, AIDS-Related Pain, AnkylosingSpondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic CerebralPalsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain,Behcet's Disease (Syndrome), Burning Mouth Syndrome, Bursitis, CancerPain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome,Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease,Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain(CFAP), Chronic Pain, Chronic Pancreatitis, Chronic Pelvic PainSyndrome, Collapsed Lung (Pneumothorax), Complex Regional Pain Syndrome(RSD), Corneal Neuropathic Pain, Crohn's Disease, Degenerative DiscDisease, Dental Pain, Dercum's Disease, Dermatomyositis, DiabeticPeripheral Neuropathy (DPN), Dystonia, Ehlers-Danlos Syndrome (EDS),Endometriosis, Eosinophilia-Myalgia Syndrome (EMS), Erythromelalgia,Fibromyalgia, Gout, Headaches, Herniated disc, Hydrocephalus,Intercostal Neuraligia, Interstitial Cystitis, Irritable Bowel syndrome(IBS), Juvenile Dermatositis (Dermatomyositis), Knee Injury, Leg Pain,Loin Pain-Haematuria Syndrome, Lupus, Lyme Disease, Medullary SpongeKidney (MSK), Meralgia Paresthetica, Mesothelioma, Migraine,Musculoskeletal pain, Myofascial Pain, Myositis, Neck Pain, NeuropathicPain, Occipital Neuralgia, Osteoarthritis, Paget's Disease, ParsonageTurner Syndrome, Pelvic Pain, Periodontitis Pain, Peripheral Neuropathy,Phantom Limb Pain, Pinched Nerve, Polycystic Kidney Disease, PolymyalgiaRhuematica, Polymyositis, Porphyria, Post Herniorraphy Pain Syndrome,Post Mastectomy, Postoperative Pain, Pain Syndrome, Post Stroke Pain,Post Thorocotomy Pain Syndrome, Postherpetic Neuralgia (Shingles),Post-Polio Syndrome, Primary Lateral Sclerosis, Psoriatic Arthritis,Pudendal Neuralgia, Radiculopathy, Raynaud's Disease, RheumatoidArthritis (RA), Sacroiliac Joint Dysfunction, Sarcoidosi, Scheuemann'sKyphosis Disease, Sciatica, Scoliosis, Shingles (Herpes Zoster),Sjogren's Syndrome, Spasmodic Torticollis, Sphincter of OddiDysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal Cord Injury,Spinal Stenosis, Syringomyelia, Tarlov Cysts, Transverse Myelitis,Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis, VascularPain or Vulvodynia.
 39. The method of claim 35, wherein the inflammatoryor autoimmune disorder is chronic inflammation, mast cell activationsyndrome, Multiple Sclerosis, Steven Johnson's Syndrome, Toxic EpidermalNecrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis,dermatitis, phlebitis, reflex sympathetic dystrophy/complex regionalpain syndrome (rsd/crps), rhinitis, tendonitis, tonsillitis, acnevulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease,reactive airway disorder, asthma, airway infection, autoinflammatorydisease, celiac disease, chronic prostatitis, diverticulitis,glomerulonephritis, hidradenitis suppurativa, hypersensitivities,intestinal disorder, epithelial intestinal disorder, inflammatory boweldisease, irritable bowel syndrome, Crohn's Disease, ulcerative colitis,lupus erythematous, interstitial cystitis, otitis, pelvic inflammatorydisease, endometrial pain, reperfusion injury, rheumatic fever,rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lunginflammation, chronic obstructive pulmonary disease, cardiovasculardisease, or vasculitis.